Japan Approvals Include World-First For Skyrizi, Kymriah As Asia's First CAR-T
Executive Summary
Japan approves a large batch of new products including significant first nods globally for AbbVie's antibody for psoriasis and Japan's first gene-based therapy, as well as a pioneering first approval in Asia for a CAR-T drug.
The latest batch of product approvals in Japan includes the first to be granted anywhere globally for AbbVie Inc.'s anti-interleukin-23 antibody Skyrizi (risankizumab), as well as nods for Japan’s first gene-based therapy and a pioneering marketing clearance in Asia for a CAR-T drug, Novartis AG's Kymriah.
Skyrizi, being developed globally in a collaboration with Boehringer Ingelheim GmbH, was approved for plaque psoriasis, generalized pustular psoriasis, erythrodermic psoriasis and psoriatic arthritis in adults with an inadequate response to conventional therapies.
The formal clearance, issued by the country’s ministry of health, labour and welfare, was based on data from a suite of Japanese Phase II/III trials (sustaIMM, ultIMMA-1 and IMMspire), as well as a global Phase II study in active psoriatic arthritis.
The full Japanese approval follows a positive opinion (initial recommendation) issued in February in Europe, for the specific indication of adult moderate to severe plaque psoriasis, while an approval decision in the US is expected in the first half of this year.
AbbVie – which is looking to the product to help offset revenue challenges for its blockbuster biologic Humira (adalimumab) - is leading development and commercialization efforts globally, but the new therapy will enter what is already a crowded psoriasis marketplace.
The company noted that in Japan as many as 15% of individuals with psoriasis also develop psoriatic arthritis.
Kymriah, Collategene Break New Ground
In another significant decision, the ministry formally endorsed an advisory panel's approval recommendation for Kymria (tisagenlecleucel), for the treatment of two distinct indications – CD19-positive relapsed or refractory B-cell acute lymphoblastic leukemia and CD19-positive relapsed/refractory diffuse large B-cell lymphoma. The approval will extend the global reach of the chimeric antigen receptor T cell (CAR-T) therapy following on from its existing regulatory authorizations in the US, Europe (including Switzerland), Canada and Australia.
The product, which is administered only once, becomes the first and so far only CAR-T therapy to receive regulatory approval in Asia for these two B-cell malignancies, and the clearance was based on a review of data from the global clinical trials JULIET and ELIANA, which included sites in Japan.
In another step forward in the cell and gene therapy area, but after a protracted development process, Japanese venture AnGes Inc. finally received a conditional approval for its hepatocyte growth factor (HGF) plasmid gene therapy, Collategene (beperminogene perplasmid; AMG0001), for critical limb ischemia.
The clearance follows a January 2018 filing, and more specifically is for the improvement of ulcers in patients with chronic arterial occlusion (arteriosclerosis obliterans and Buerger's disease) with an inadequate response to standard therapy and who have difficulty in revascularization. An estimated 150,000 patients in Japan are estimated to be affected annually by limb ischemia, AnGes noted.
The DNA plasmid encodes the HGF gene to promote local angiogenesis and is administered intramuscularly into the lower limbs. Sales and marketing rights in Japan (and the US) are held by Mitsubishi Tanabe Pharma Corp..
As is standard practice, the conditional approval requires the conduct of an all-patient safety and efficacy monitoring program.
Eyes On Pricing
Following the approvals of the two novel cell and gene therapies, all eyes are now on the price-setting process and what reimbursement prices will be granted under Japan's national health insurance scheme (which grants national coverage and access), given the generally high levels that such products are commanding elsewhere. Kymriah is priced at close to half a million dollars in the US.
Following ministry approval, reimbursement prices are usually discussed and set within several months, and Kymriah and Collategene could see this happening as early as May, which would be the last step before their launch in Japan.
Whether Novartis may offer novel financing schemes is unknown at this stage, but there have been some indications that the prices of new cell and gene therapies may come in for more official scrutiny, despite a generally highly supportive policy and regulatory environment in Japan for such products.
The issue has been thrown into relief recently following the approval and subsequent reimbursement of a somewhat controversial stem cell therapy for spinal cord injury. (Also see "Cell Therapies Forge Ahead In Japan with Reimbursement, Approval Decisions " - Scrip, 21 Feb, 2019.)
Erleada, Biktarvy
Other products in the group of approvals included Janssen Pharmaceutical Cos.'s oral androgen receptor signal inhibitor Erleada (apalutamide 60mg), for adults with castration-resistant prostate cancer without distant metastases, and Gilead Sciences Inc.' once-daily, single-tablet regimen for HIV-1 Biktarvy.
The first product, approved in the US in February 2018, will be co-promoted with Nippon Shinyaku Co. Ltd., while Biktarvy combines bictegravir 50mg, an unboosted integrase strand transfer inhibitor, with the established combination of emtricitabine 200mg and tenofovir alafenamide 25mg, which is already marketed as Descovy.
Approved in the US in February 2018, Biktarvy will become the first HIV therapy for Gilead to launch directly in Japan through its own subsidiary. Late last year, the US firm also regained local rights to six HIV drugs (other than Biktarvy) that had been licensed to Japan Tobacco Inc. under an earlier alliance. (Also see "Asia Deal Watch: Takeda, Eisai Team With Non-Profit On Review Of Novel Targets For Antibiotics" - Scrip, 12 Dec, 2018.)
Sumitomo Dainippon Pharma Co. Ltd.'s alkylating agent Rithio (thiotepa 100mg) infusion was approved for conditioning treatment prior to autologous hematopoietic stem cell transplantation for pediatric malignant solid tumors.
A previous marketing authorization (as Tespamin) was withdrawn in 2010 after following discontinued manufacturing of the active ingredient, but the ministry requested companies to develop the drug following requests from patients and doctors.
SDP said it is also planning a filing as a conditioning treatment prior to auto-HSCT for malignant lymphoma.
Other approvals were given to Shionogi & Co. Ltd.’s Vyvanse (lisdexamfetamine; licensed from Shire PLC/Takeda Pharmaceutical Co. Ltd.) for pediatric attention-deficit hyperactivity disorder, filed in April 2017, Merck Sharp & Dohme Ltd.'s fixed-dose combination Rosuzet (ezetimibe and rosuvastatin), and CSL Ltd.’s immunoglobulin products Hizentra (subcutaneous) and Privigen (intravenous), for the autoimmune disorder chronic inflammatory demyelinating polyneuropathy.
ADA Drug, Biosimilar
Teijin Pharma Ltd. meanwhile said it had acquired marketing approval for orphan drug Revcovi for intramuscular injection (elapegademase 2.4mg), for adenosine deaminase (ADA) deficiency, an ultra-rare and often fatal disease caused by a lack of enzyme activity due to gene mutations. The company has exclusive development and marketing rights in Japan to the drug, originally developed by UK firm Leadiant Biosciences Inc. (formerly Sigma-Tau Pharma).
The disorder, which leads to lymphocyte reduction and severe combined immunodeficiency, is an officially designated intractable disease in Japan, with an estimated annual incidence of 1/200,000 and 1/1,000,000 live births, and Revcovi was designated as an orphan drug in Japan in March 2016.
The first-line treatment option for ADA deficiency is hematopoietic stem cell transplantation, and other options include ADA enzyme replacement therapy for improvement in immune function and gene therapy. Revcovi, a recombinant adenosine deaminase analogue chemically modified with polyethylene glycol, becomes the first ADA enzyme replacement therapy to be approved in the country, following a government request. Teijin Pharma submitted its approval application in June 2018.
YL Biologics Ltd. and Teijin also said they had obtained manufacturing and sales approval for their etanercept biosimilar (YLB113) for rheumatoid arthritis and polyarticular-course juvenile idiopathic arthritis, which YL Biologics is developing globally.
YL Biologics led a global Phase III study in over 500 rheumatoid arthritis patients, half of them recruited in Japan, and based on the results submitted an NDA in March 2018. YL obtains the active pharmaceutical ingredient from India’s Lupin Ltd., but subcontracts manufacturing of it to AY Pharma Co. Ltd., a wholly owned subsidiary of Japanese contract manufacturer Yoshindo.
Yoshindo entered into a sales collaboration agreement with Teijin Pharma in July 2018 and the two firms will jointly distribute and market YLB113 in Japan.
All these new products are also still awaiting reimbursement price listing under the NHI system, which again should follow within several months and if granted would nationwide launches.
Multiple New Indications
Adding to the new products was a group of clearances of additional indications for existing drugs, including AstraZeneca PLC’s oral, once-daily selective inhibitor of human sodium-glucose co-transporter 2 (SGLT2) Forxiga (dapagliflozin), as an oral adjunct treatment to insulin for adults with type-1 diabetes whose glucose levels are not adequately controlled with insulin alone. The product will be distributed by Ono Pharmaceutical Co. Ltd.
The approval was based on data from the Phase III DEPICT clinical program and a dedicated trial in Japanese patients, and follows closely an approval from the European Commission on March 20, as an adjunct treatment to insulin in adults with type 1 diabetes. It is also under regulatory review in the US for the same indication, with a decision expected in the second half of 2019.
In Japan, the number of type 1 patients with no insulin secretion is estimated by the health ministry at 100,000-140,000.
Pfizer Inc.'s Rheumatrex (methotrexate) was approved for psoriasis vulgaris unresponsive to topical treatment, and arthritic psoriasis, pustular psoriasis and psoriatic erythroderma, following a government development request. The company's Vyndaquel (tafamidis) was also cleared for transthyretin cardiac amyloidosis (wild-type and mutant) and ATTR-cardiac amyloidosis
Sanofi’s Dupixent (dupilumab) was approved for bronchial asthma, Ono's Onoact (landiolol) for ventricular arrhythmia, Chugai Pharmaceutical Co. Ltd. 's Rituxan (rituximab) for CD20-positive chronic lymphocytic leukemia and Actemra (tocilizumab) for cytokine release syndrome.
Meanwhile, SymBio Pharmaceuticals Ltd.'s Treakisym (bendamustine) gained a nod for additional use as a pretreatment to adoptive T-cell therapy, enabling it to be used ahead of treatment with Kymriah. The drug is already approved and marketed through Eisai Co. Ltd. for uses including chronic lymphocytic leukemia and relapsed/refractory low-grade B-cell non-Hodgkin's lymphoma.
From the editors of PharmAsia News.