• facebook
  • linkedin
  • youtube

Recently, three gene therapy drugs have been approved for marketing, namely: (1) On July 21, 2022, PTC Therapeutics, Inc. (NASDAQ: PTCT) announced that its AAV gene therapy Upstaza™ was approved by the European Commission It is the first marketed gene therapy directly injected into the brain (see previous articles: Another Milestone in Gene Therapy | The world's first AAV gene therapy directly injected into the brain is approved for marketing). (2) On August 17, 2022, the U.S. Food and Drug Administration (FDA) approved Bluebird Bio’s gene therapy Zynteglo (betibeglogene autotemcel, beti-cel) for the treatment of beta thalassemia. The approval of the therapy in the United States is undoubtedly a "help in the snow" for Bluebird Bio, which is in financial crisis. (3) On August 24, 2022, BioMarin Pharmaceutical (BioMarin) announced that the European Commission approved the conditional marketing of ROCTAVIAN™ (valoctocogene roxaparvovec), a gene therapy for hemophilia A, for the treatment of patients with no history of FVIII factor inhibitors and negative AAV5 antibodies adult patients with severe hemophilia A (see previous article: Heavy! BioMarin's hemophilia A gene therapy approved for marketing). So far, 41 gene therapy drugs have been approved for marketing worldwide.

Gene is the basic genetic unit that controls traits. Except for the genes of some viruses, which are composed of RNA, the genes of most organisms are composed of DNA. Most diseases of the organism are caused by the interaction between genes and the environment, and many diseases can be cured or alleviated in essence through gene therapy. Gene therapy is considered to be a revolution in the field of medicine and pharmacy. The broad gene therapy drugs include drugs based on DNA-modified DNA drugs (such as viral vector-based in vivo gene therapy drugs, in vitro gene therapy drugs, naked plasmid drugs, etc.) and RNA drugs (such as antisense oligonucleotide drugs, siRNA drugs, and mRNA gene therapy, etc.); narrowly defined Gene therapy drugs mainly include plasmid DNA drugs, gene therapy drugs based on viral vectors, gene therapy drugs based on bacterial vectors, gene editing systems and cell therapy drugs that are genetically modified in vitro. After years of tortuous development, gene therapy drugs have achieved inspiring clinical results. (excluding DNA vaccines and mRNA vaccines), 41 gene therapy drugs have been approved for marketing in the world. With the launch of products and the rapid development of gene therapy technology, gene therapy is about to usher in a period of rapid development.

worldwide1

Classification of gene therapy (Image source: Biological Jingwei)

This article lists 41 gene therapies that have been approved for marketing (excluding DNA vaccines and mRNA vaccines).

1. In vitro gene therapy

(1) Strimvelis

Company: Developed by GlaxoSmithKline (GSK).

Time to market: Approved by the European Union in May 2016.

Indications: For the treatment of severe combined immunodeficiency (SCID).

Remarks: The general process of this therapy is to first obtain the patient's own hematopoietic stem cells, expand and culture them in vitro, and then use retrovirus to introduce a copy of the functional ADA (adenosine deaminase) gene into their hematopoietic stem cells, and finally transfer the modified hematopoietic stem cells. Hematopoietic stem cells are infused back into the body. Clinical results showed that the 3-year survival rate of ADA-SCID patients treated with Strimvelis was 100%.

(2) Zalmoxis

Company: Produced by MolMed, Italy.

Time to market: Obtained EU conditional marketing authorization in 2016.

Indications: It is used for adjuvant therapy of the immune system of patients after hematopoietic stem cell transplantation.

Remarks: Zalmoxis is an allogeneic T cell suicide gene immunotherapy modified by retroviral vector. The 1NGFR and HSV-TK Mut2 suicide genes allow people to use ganciclovir at any time to kill T cells that cause adverse immune responses, prevent further deterioration of GVHD that may occur, and restore immune function in patients with haploidentical HSCT after surgery Escort.

(3) Invossa-K

Company: Developed by TissueGene (KolonTissueGene) company.

Time to market: Approved for listing in South Korea in July 2017.

Indications: For the treatment of degenerative knee arthritis.

Remarks: Invossa-K is an allogeneic cell gene therapy involving human chondrocytes. Allogeneic cells are genetically modified in vitro, and the modified cells can express and secrete transforming growth factor β1 (TGF-β1) after intra-articular injection. β1), thereby improving the symptoms of osteoarthritis. Clinical results show that Invossa-K can significantly improve knee arthritis. The license was revoked by South Korea's drug regulator in 2019 because the manufacturer incorrectly labelled the ingredients used.

(4) Zynteglo

Company: Developed by the American bluebird bio (bluebird bio) company.

Time to market: Approved by the European Union in 2019, and approved by the FDA in August 2022.

Indications: For the treatment of transfusion-dependent β-thalassemia.

Remarks: Zynteglo is a lentiviral in vitro gene therapy, which uses a lentiviral vector to introduce a functional copy of the normal β-globin gene (βA-T87Q-globin gene) into hematopoietic stem cells removed from patients. , and then infuse these genetically modified autologous hematopoietic stem cells back into the patient. Once the patient has a normal βA-T87Q-globin gene, they may produce a normal HbAT87Q protein, which can effectively reduce or eliminate the need for blood transfusions. It's a one-time therapy designed to replace lifelong blood transfusions and lifelong medications for patients 12 years of age and older.

(5) Skysona

Company: Developed by the American bluebird bio (bluebird bio) company.

Time to market: Approved by the EU for marketing in July 2021.

Indications: For the treatment of early cerebral adrenoleukodystrophy (CALD).

Remarks: Skysona gene therapy is the only one-time gene therapy approved for the treatment of early cerebral adrenoleukodystrophy (CALD). Skysona (elivaldogene autotemcel, Lenti-D) is a hematopoietic stem cell lentiviral in vitro gene therapy Lenti-D. The general process of the therapy is as follows: autologous hematopoietic stem cells are taken out from the patient, modified in vitro by lentivirus carrying the human ABCD1 gene, and then infused back into the patient. For the treatment of patients under the age of 18 with ABCD1 gene mutation and CALD.

(6) Kymriah

Company: Developed by Novartis.

Time to market: Approved by the FDA in August 2017.

Indications: Treatment of precursor B-cell acute lymphoblastic leukemia (ALL) and relapsed and refractory DLBCL.

Remarks: Kymriah is a lentiviral in vitro gene therapy drug, the world's first approved CAR-T therapy, targeting CD19 and using the co-stimulatory factor 4-1BB. Pricing is $475,000 in the U.S. and $313,000 in Japan.

(7) Yescarta

Company: Developed by Kite Pharma, a subsidiary of Gilead.

Time to market: Approved by the FDA in October 2017.

Indications: For the treatment of relapsed or refractory large B-cell lymphoma.

Remarks: Yescarta is a retroviral in vitro gene therapy. It is the second CAR-T therapy approved in the world. It targets CD19 and uses the costimulatory factor of CD28. Pricing in the US is $373,000.

(8) Tecartus

Company: Developed by Gilead (GILD).

Time to market: Approved by the FDA in July 2020.

Indications: For relapsed or refractory mantle cell lymphoma.

Remarks: Tecartus is an autologous CAR-T cell therapy targeting CD19, and is the third CAR-T therapy approved for marketing in the world.

(9) Breyanzi

Company: Developed by Bristol-Myers Squibb (BMS).

Time to market: Approved by the FDA in February 2021.

Indications: Relapsed or refractory (R/R) large B-cell lymphoma (LBCL).

Remarks: Breyanzi is an in vitro gene therapy based on lentivirus, and the fourth CAR-T therapy approved for marketing in the world, targeting CD19. The approval of Breyanzi is a milestone for Bristol-Myers Squibb in the field of cellular immunotherapy, which Bristol-Myers acquired when it acquired Celgene for $74 billion in 2019.

(10) Abecma

Company: Co-developed by Bristol-Myers Squibb (BMS) and bluebird bio.

Time to market: Approved by the FDA in March 2021.

Indications: Relapsed or refractory multiple myeloma.

Remarks: Abecma is a lentivirus-based in vitro gene therapy, the world's first CAR-T cell therapy targeting BCMA, and the fifth CAR-T therapy approved by the FDA. The drug principle is to express the chimeric BCMA receptor on the patient's autologous T cells through lentivirus-mediated genetic modification in vitro. Before the infusion of the cell gene drug, the patient received two compounds of cyclophosphamide and fludarabine for pre-treatment. Treatment to remove unmodified T cells from the patient, and then infuse the modified T cells back into the patient's body to seek out and kill BCMA-expressing cancer cells.

(11) Libmeldy

Company: Developed by Orchard Therapeutics.

Time to market: Approved by the European Union for listing in December 2020.

Indications: For the treatment of metachromatic leukodystrophy (MLD).

Remarks: Libmeldy is a gene therapy based on lentiviral in vitro gene modification of autologous CD34+ cells. Clinical data show that a single intravenous infusion of Libmeldy is effective in modifying the course of early-onset MLD and severe motor and cognitive impairment in untreated patients of the same age.

(12) Benoda

Company: Developed by WuXi Junuo.

Time to market: Officially approved by NMPA in September 2021.

Indications: Treatment of relapsed or refractory large B-cell lymphoma (r/r LBCL) in adult patients after second-line or more systemic therapy.

Remarks: Benoda is an anti-CD19 CAR-T gene therapy, and it is also the core product of WuXi Junuo. It is the second CAR-T product approved in China, except for relapsed/refractory large B-cell lymphoma. In addition, WuXi Junuo also plans to develop Ruiki Orenza injection for the treatment of various other indications, including follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL) , second-line diffuse large B-cell lymphoma (DLBCL) and acute lymphoblastic leukemia (ALL).

(13) CARVYKTI

Company: Legend Bio's first approved product.

Time to market: Approved by the FDA in February 2022.

Indications: Treatment of relapsed or refractory multiple myeloma (R/R MM).

Remarks: CARVYKTI (ciltacabtagene autoleucel, referred to as Cilta-cel) is a CAR-T cell immune gene therapy with two single-domain antibodies targeting B cell maturation antigen (BCMA). The data show that CARVYKTI demonstrated an overall response rate of up to 98% in patients with relapsed or refractory multiple myeloma who had received four or more prior therapies, including proteasome inhibitors, immunomodulators, and anti-CD38 monoclonal antibodies.

2. In vivo gene therapy based on viral vectors

(1) Gendicine/born again

Company: Developed by Shenzhen Saibainuo Company.

Time to market: Approved for listing in China in 2003.

Indications: For the treatment of squamous cell carcinoma of the head and neck.

Remarks: Recombinant human p53 adenovirus injection Gendicine/Jinshengsheng is an adenovirus vector gene therapy drug with independent intellectual property rights owned by Shenzhen Saibainuo Company. The drug is composed of normal human tumor suppressor gene p53 and artificially modified recombinant replication-deficient Human adenovirus type 5 is composed of human adenovirus type 5. The former is the main structure of the drug to exert anti-tumor effect, and the latter mainly acts as a carrier. The adenovirus vector carries the therapeutic gene p53 into the target cell, and expresses the tumor suppressor gene p53 in the target cell. The product can up-regulate various anti-cancer genes and down-regulate the activities of various oncogenes, thereby enhancing the anti-tumor effect of the body and achieving the purpose of killing tumors.

(2) Rigvir

Company: Developed by Latvian company Latima.

Time to market: Approved in Latvia in 2004.

Indications: For the treatment of melanoma.

Remarks: Rigvir is a gene therapy based on a gene-modified ECHO-7 enterovirus vector, which has been used in Latvia, Estonia, Poland, Armenia, Belarus and other places, and is also being registered with the EMA of the European Union. . Clinical cases over the past ten years have proved that Rigvir oncolytic virus is safe and effective, and can improve the survival rate of melanoma patients by 4-6 times. In addition, the therapy is also suitable for a variety of other cancers, including colorectal cancer, pancreatic cancer, bladder cancer. cancer, kidney cancer, prostate cancer, lung cancer, uterine cancer, lymphosarcoma, etc.

(3) Oncorine/Ankerui

Company: Developed by Shanghai Sunway Biotechnology Co., Ltd.

Time to market: Approved for listing in China in 2005.

Indications: Treatment of head and neck tumors, liver cancer, pancreatic cancer, cervical cancer and other cancers.

Remarks: Oncorine is an oncolytic virus gene therapy product using adenovirus as a vector. The obtained oncolytic adenovirus can replicate specifically in tumors lacking or abnormal p53 gene, causing tumor cell lysis, thereby killing tumor cells. without damaging normal cells. Clinical results show that Anke Rui has good safety and efficacy for a variety of malignant tumors.

(4) Glybera

Company: Developed by uniQure.

Time to market: Approved in Europe in 2012.

Indications: Treatment of lipoprotein lipase deficiency (LPLD) with severe or recurrent episodes of pancreatitis despite a strictly restricted fat diet.

Remarks: Glybera (alipogene tiparvovec) is a gene therapy drug based on AAV as a vector. This therapy uses AAV as a vector to transfer the therapeutic gene LPL into muscle cells, so that the corresponding cells can produce a certain amount of lipoprotein lipase, It plays a role in relieving disease, and this therapy is effective for a long time after one administration (the effect can last for many years). The drug was delisted in 2017, and the reasons for its delisting may be related to two factors: too high pricing and limited market demand. The average cost of a single treatment of the drug is as high as 1 million US dollars, and only one patient has purchased and used it so far. Although the medical insurance company reimbursed it for 900,000 US dollars, it is also a large burden for the insurance company. In addition, the indication for the drug is too rare, with an incidence rate of about 1 in 1 million and a high rate of misdiagnosis.

(5) Imlygic

Company: Developed by Amgen.

Time to market: In 2015, it was approved for listing in the United States and the European Union.

Indications: Treatment of melanoma lesions that cannot be completely removed by surgery.

Remarks: Imlygic is a genetically modified (deleting its ICP34.5 and ICP47 gene fragments, and inserting the human granulocyte-macrophage colony-stimulating factor GM-CSF gene into the virus) attenuated herpes simplex virus type 1 (HSV-1) oncolytic virus, the first FDA-approved oncolytic virus gene therapy. The method of administration is intralesional injection. Direct injection into melanoma lesions can cause the rupture of tumor cells and release tumor-derived antigens and GM-CSF to promote anti-tumor immune responses.

(6) Luxturna

Company: Developed by Spark Therapeutics, a Roche subsidiary.

Time to market: Approved by the FDA in 2017, and then approved for marketing in Europe in 2018.

Indications: For the treatment of children and adults with vision loss due to mutations in the double copy of the RPE65 gene but with sufficient numbers of viable retinal cells.

Remarks: Luxturna is an AAV-based gene therapy that is administered by subretinal injection. The gene therapy uses AAV2 as a carrier to introduce a functional copy of the normal RPE65 gene into the retinal cells of the patient, so that the corresponding cells express the normal RPE65 protein to compensate for the defect of the patient's RPE65 protein, thereby improving the patient's vision.

(7) Zolgensma

Company: Developed by AveXis, a subsidiary of Novartis.

Time to market: Approved by the FDA in May 2019.

Indications: Treatment of spinal muscular atrophy (Spinal Muscular Atrophy, SMA) patients under 2 years old.

Remarks: Zolgensma is a gene therapy based on AAV vector. This drug is the only one-time treatment plan for spinal muscular atrophy approved for marketing in the world. page, is a milestone progress. This gene therapy uses the scAAV9 vector to introduce the normal SMN1 gene into patients via intravenous infusion, producing normal SMN1 protein, thereby improving the function of affected cells such as motor neurons. In contrast, the SMA drugs Spinraza and Evrysdi require repeated dosing over a long period of time, with Spinraza administered as a spinal injection every four months, and Evrysdi, a daily oral drug.

(8) Delytact

Company: Developed by Daiichi Sankyo Company Limited (TYO: 4568).

Time to market: Conditional approval from the Japanese Ministry of Health, Labour and Welfare (MHLW) in June 2021.

Indications: For the treatment of malignant glioma.

Remarks: Delytact is the fourth oncolytic virus gene therapy product approved globally and the first oncolytic virus product approved for the treatment of malignant glioma. Delytact is a genetically engineered herpes simplex virus type 1 (HSV-1) oncolytic virus developed by Dr. Todo and colleagues. Delytact introduces an additional deletion mutation into the G207 genome of second-generation HSV-1, enhancing its selective replication in cancer cells and the induction of anti-tumor immune responses, while maintaining a high safety profile. Delytact is the first third-generation oncolytic HSV-1 currently in clinical evaluation. The approval of Delytact in Japan was based on a single-arm Phase 2 clinical trial. In patients with recurrent glioblastoma, Delytact met the primary endpoint of one-year survival, and the results showed that Delytact performed better than G207. Strong replication and higher antitumor activity. This is effective in solid tumor models including breast, prostate, schwannoma, nasopharyngeal, hepatocellular, colorectal, malignant peripheral nerve sheath tumors and thyroid cancer.

(9) Upstaza

Company: Developed by PTC Therapeutics, Inc. (NASDAQ: PTCT).

Time to market: Approved by the EU in July 2022.

Indication: For aromatic L-amino acid decarboxylase (AADC) deficiency, approved for the treatment of patients 18 months of age and older.

Remarks: Upstaza™ (eladocagene exuparvovec) is an in vivo gene therapy using adeno-associated virus type 2 (AAV2) as a vector. The patient is diseased due to a mutation in the gene encoding the AADC enzyme. AAV2 carries a healthy gene encoding the AADC enzyme. The therapeutic effect is achieved in the form of genetic compensation. In theory, a single dose is effective for a long time. It is the first marketed gene therapy directly injected into the brain. The marketing authorization is applicable to all 27 EU member states, as well as Iceland, Norway and Liechtenstein.

(9) Roctavian

Company: Developed by BioMarin Pharmaceutical (BioMarin).

Time to market: Approved by the EU in August 2022.

Indications: For the treatment of adult patients with severe hemophilia A without a history of FVIII factor inhibition and AAV5 antibody negative.

Remarks: Roctavian (valoctocogene roxaparvovec) uses AAV5 as the vector and uses the human liver-specific promoter HLP to drive the expression of human coagulation factor eight (FVIII) with the B domain deleted. The decision of the European Commission to approve the marketing of valoctocogene roxaparvovec is based on the overall data of the drug's clinical development program. Among them, the phase III clinical trial GENEr8-1 showed that compared with the data of the year before enrollment, after a single infusion of valoctocogene roxaparvovec, Subjects had a significantly lower annual bleeding rate (ABR), less frequent use of recombinant factor VIII (F8) protein preparations, or a significant increase in F8 activity in the body's blood. After 4 weeks of treatment, subjects' annual F8 use and ABR requiring treatment were reduced by 99% and 84%, respectively, a statistically significant difference (p<0.001). The safety profile was favorable, with no subjects experiencing F8 factor inhibition, malignancy, or thrombotic side effects, and no treatment-related serious adverse events (SAEs) were reported.

3. Small nucleic acid drugs

(1) Vitravene

Company: Jointly developed by Ionis Pharma (formerly Isis Pharma) and Novartis.

Time to market: Approved by FDA and EU EMA in 1998 and 1999.

Indications: For the treatment of cytomegalovirus retinitis in HIV-positive patients.

Remarks: Vitravene is an antisense oligonucleotide drug and the first oligonucleotide drug approved for marketing in the world. At the beginning of the market, the market demand for anti-cytomegalovirus drugs was very urgent; then due to the development of highly active antiretroviral therapy, the number of cytomegalovirus cases dropped sharply. Due to the low market demand, the drug was released in 2002 and 2006 Withdrawal in EU countries and the US.

(2) Macugen

Company: Co-developed by Pfizer and Eyetech.

Time to market: Approved for listing in the United States in 2004.

Indications: For the treatment of neovascular age-related macular degeneration.

Remarks: Macugen is a pegylated modified oligonucleotide drug that can target and bind to vascular endothelial growth factor (VEGF165 isoform), and is administered by intravitreal injection.

(3) Defitelio

Company: Developed by Jazz.

Time to market: Approved by the European Union in 2013, and approved by the FDA in March 2016.

Indications: For the treatment of hepatic venule occlusive disease associated with renal or pulmonary dysfunction after hematopoietic stem cell transplantation.

Remarks: Defitelio is an oligonucleotide drug, a mixture of oligonucleotides with plasmin properties. It was withdrawn in 2009 for commercial reasons.

(4) Kynamro

Company: Co-developed by Ionis Pharma and Kastle.

Time to market: Approved in the United States as an orphan drug in 2013.

Indications: For the adjuvant treatment of homozygous familial hypercholesterolemia.

Remarks: Kynamro is an antisense oligonucleotide drug, an antisense oligonucleotide targeting human apo B-100 mRNA. Kynamro is administered as 200 mg subcutaneously once a week.

(5) Spinraza

Company: Developed by Ionis Pharmaceuticals.

Time to market: Approved by the FDA in December 2016.

Indications: For the treatment of spinal muscular atrophy (SMA).

Remarks: Spinraza (nusinersen) is an antisense oligonucleotide drug. Spinraza can change the RNA splicing of SMN2 gene by binding to the splicing site of SMN2 exon 7, thereby increasing the production of fully functional SMN protein . In August 2016, BIOGEN Corporation exercised its option to acquire Spinraza's global rights. Spinraza began its first clinical trial in humans in 2011. In just 5 years, it was approved by the FDA in 2016, reflecting the FDA's full recognition of its efficacy. The drug was approved for marketing in China in April 2019. The entire approval cycle of Spinraza in China is less than 6 months. It has been 2 years and 2 months since Spinraza was first approved in the United States. Such a blockbuster foreign rare disease new drug is in The speed of listing in China is already very fast. This is also due to the "Notice on the Release of the First List of Overseas New Drugs Urgently Needed for Clinical Research" issued by the Center for Drug Evaluation on November 1, 2018, which was included in the first batch of 40 key foreign new drugs for accelerated review, and Spinraza ranked in.

(6) Exondys 51

Company: Developed by AVI BioPharma (later renamed Sarepta Therapeutics).

Time to market: Approved by the FDA in September 2016.

Indications: For the treatment of Duchenne muscular dystrophy (DMD) with DMD gene mutation in exon 51 skipping gene.

Remarks: Exondys 51 is an antisense oligonucleotide drug. The antisense oligonucleotide can bind to the exon 51 position of the pre-mRNA of the DMD gene, resulting in the formation of mature mRNA. Excision, thereby partially correcting the mRNA reading frame, helps the patient to synthesize some functional forms of dystrophin that are shorter than the normal protein, thereby improving the patient's symptoms.

(7) Tegsedi

Company: Developed by Ionis Pharmaceuticals.

Time to market: Approved by the European Union for marketing in July 2018.

Indications: For the treatment of hereditary transthyretin amyloidosis (hATTR).

Remarks: Tegsedi is an antisense oligonucleotide drug targeting transthyretin mRNA. It is the world's first approved drug for the treatment of hATTR. The method of administration is subcutaneous injection. The drug reduces the production of ATTR protein by targeting the mRNA of transthyretin (ATTR), and has a good benefit-risk ratio in the treatment of ATTR. Neither disease stage nor presence of cardiomyopathy was relevant.

(8) Onpattro

Company: Co-developed by Alnylam and Sanofi.

Time to market: Approved for listing in the United States in 2018.

Indications: For the treatment of hereditary transthyretin amyloidosis (hATTR).

Remarks: Onpattro is an siRNA drug targeting transthyretin mRNA, which reduces the production of ATTR protein in the liver and the accumulation of amyloid deposits in peripheral nerves by targeting the mRNA of transthyretin (ATTR). , thereby improving and relieving disease symptoms.

(9) Givlaari

Company: Developed by Alnylam Corporation.

Time to market: Approved by the FDA in November 2019.

Indications: For the treatment of acute hepatic porphyria (AHP) in adults.

Remarks: Givlaari is an siRNA drug, the second siRNA drug approved for marketing after Onpattro. The drug is administered subcutaneously and targets the mRNA for degradation of the ALAS1 protein. Monthly Givlaari treatment can significantly and persistently reduce the level of ALAS1 in the liver, thereby reducing the levels of neurotoxic ALA and PBG to the normal range, thereby Relieve the patient's disease symptoms. The data showed that patients treated with Givlaari had a 74% reduction in the number of disease flares compared to the placebo group.

(10) Vyondys53

Company: Developed by Sarepta Therapeutics.

Time to market: Approved by the FDA in December 2019.

Indication: For the treatment of DMD patients with dystrophin gene exon 53 splice mutation.

Remarks: Vyondys 53 is an antisense oligonucleotide drug. The oligonucleotide drug targets the splicing process of dystrophin mRNA precursor. In the indirect process of dystrophin mRNA precursor, the external Exon 53 was partially spliced out, i.e. not present on mature mRNA, and was designed to produce a truncated but still functional dystrophin protein, thereby improving exercise capacity in patients.

(11) Waylivra

Company: Developed by Ionis Pharmaceuticals and its subsidiary Akcea Therapeutics.

Time to market: Approved by the European Medicines Agency (EMA) in May 2019.

Indication: As an adjunctive therapy to a controlled diet in adult patients with familial chylomicronemia syndrome (FCS).

Remarks: Waylivra is an antisense oligonucleotide drug, which is the first drug approved for the treatment of FCS in the world.

(12) Leqvio

Company: Developed by Novartis.

Time to market: Approved by the EU in December 2020.

Indications: For the treatment of adult primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia.

Remarks: Leqvio is a siRNA drug targeting PCSK9 mRNA. It is the world's first cholesterol-lowering (LDL-C) siRNA therapy. The method of administration is subcutaneous injection. The drug works by RNA interference to lower PCSK9 protein levels, which in turn lowers LDL-C levels. Clinical data show that Leqvio can reduce LDL-C by approximately 50% in patients whose LDL-C levels cannot be reduced to target levels despite maximum tolerated doses of statins.

(13) Oxlumo

Company: Developed by Alnylam Pharmaceuticals.

Time to market: Approved by the EU in November 2020.

Indications: For the treatment of primary hyperoxaluria type 1 (PH1).

Remarks: Oxlumo is a siRNA drug targeting hydroxy acid oxidase 1 (HAO1) mRNA, which is administered subcutaneously. The drug was developed using Alnylam's latest enhanced stabilization chemical ESC-GalNAc conjugation technology, which enables subcutaneously administered siRNAs with greater persistence and efficacy. The drug targets the degradation or inhibition of hydroxy acid oxidase 1 (HAO1) mRNA, reduces the level of glycolate oxidase in the liver, and then consumes the substrate required for the production of oxalate and reduces the production of oxalate to control disease progression and improve disease symptoms in patients.

(14) Viltepso

Company: Developed by NS Pharma, a subsidiary of Nippon Shinyaku.

Time to market: Approved by the FDA in August 2020.

Indications: For the treatment of Duchenne muscular dystrophy (DMD) with DMD gene mutation in exon 53 skipping gene.

Remarks: Viltepso is a phosphorodiamide morpholino oligonucleotide drug. This oligonucleotide drug can bind to the exon 53 position of the pre-mRNA of the DMD gene, resulting in the formation of mature mRNA. The exon is partially removed, thereby partially correcting the mRNA reading frame, helping the patient to synthesize some functional forms of dystrophin that are shorter than the normal protein, thereby improving the patient's symptoms.

(15) Amvuttra (vutrisiran)

Company: Developed by Alnylam Pharmaceuticals.

Time to market: Approved by the FDA in June 2022.

Indications: For the treatment of adult hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN).

Remarks: Amvuttra (Vutrisiran) is a siRNA drug targeting transthyretin (ATTR) mRNA, which is administered by subcutaneous injection. Vutrisiran is designed based on Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc conjugated delivery platform with increased potency and metabolic stability. The approval of the therapy is based on 9-month data from its Phase III clinical study (HELIOS-A), with overall results showing that the therapy improved symptoms of hATTR-PN, with more than 50% of patients reversing or stopping progression.

4. Other gene therapy drugs

(1) Rexin-G

Company: Developed by Epeius Biotech.

Time to market: Approved by the Philippine Food and Drug Administration (BFAD) in 2005.

Indications: For the treatment of advanced cancers that are resistant to chemotherapy.

Remarks: Rexin-G is a gene-loaded nanoparticle injection. It introduces the cyclin G1 mutant gene into target cells through retroviral vector to specifically kill solid tumors. The method of administration is intravenous infusion. As a tumor-targeted drug that actively seeks and destroys metastatic cancer cells, it has a certain effect on patients who are ineffective against other cancer drugs, including targeted biologics.

(2) Neovasculgen

Company: Developed by Human stem cells institute.

Listing time: Approved for listing in Russia on December 7, 2011, and then listed in Ukraine in 2013.

Indications: For the treatment of peripheral arterial disease, including severe limb ischemia.

Remarks: Neovasculgen is a DNA plasmid-based gene therapy in which the vascular endothelial growth factor (VEGF) 165 gene is constructed on a plasmid backbone and infused into patients.

(3) Collategene

Company: Co-developed by Osaka University and venture capital firms.

Listing time: Approved by the Japanese Ministry of Health, Labour and Welfare for listing in August 2019.

Indications: Treatment of severe lower extremity ischemia.

Remarks: Collategene is a plasmid-based gene therapy, the first native Japanese gene therapy drug produced by AnGes. The main component of this drug is a naked plasmid containing the gene sequence of human hepatocyte growth factor (HGF). If the drug is injected into the muscles of the lower limbs, the expressed HGF will promote the formation of new blood vessels around the occluded blood vessels. Clinical trials have confirmed its effectiveness in improving ulcers.

END


Post time: Nov-10-2022