Oncology Dominates Japan Approvals, Though Overall Tally Is Lower

Although it approved fewer new products last fiscal year, Japan granted access to a number of important new therapies, including in oncology and several for the first time worldwide, helped by continuing reforms at its regulatory body.

While the number of new active ingredients approved in Japan dipped last fiscal year, a number of important new therapies, notably in oncology, were granted regulatory clearance by the country's expanding regulatory body.

The Pharmaceuticals and Medical Devices Agency (PMDA) approved 39 new active ingredients (including several diagnostics) in the fiscal year to March 31, 2016, down from 52 in the previous year but nevertheless including a number of products in high-need areas.

In an indication of its advanced independent review capabilities, the regulator also granted a couple of world first approvals during the period. Merck Sharp & Dohme Ltd.'s once-weekly DPP-4 inhibitor Marizev (omarigliptin) was cleared for type 2 diabetes, while Shionogi & Co. Ltd.'s Mulpleta (lusutrombopag), a TPO receptor agonist, was approved for thrombocytopenia associated with chronic liver disease in patients undergoing an elective invasive procedure. (Also see "Japan First To Approve Omarigliptin, Lusutrombopag" - Scrip, 30 Sep, 2015.)

Oncology Dominates

Perhaps not surprisingly given the amount of R&D activity generally in the field across the industry, products for cancer (including one related diagnostic) accounted for 12 of the approvals during the period, making oncology the dominant therapeutic sector.

The major approvals included novel targeted therapies for both melanoma and non-small cell lung cancer, with Bristol-Myers Squibb Co.'s CTLA-4-targeting Yervoy (ipilimumab) and AstraZeneca PLC's Tagrisso (osimertinib) among the new wave of drugs being approved in Japan during the year.

The predominance of oncology also contributed to the 11 products that were approved by the PMDA for orphan indications in the period. While this was down from the 27 in the previous year, it was a reflection of manufacturers' efforts to target smaller patient populations.

Two drugs were also given expedited priority reviews for high-need uses, while US ultra-orphan company Alexion Pharmaceuticals Inc. continued its strategic expansion in Japan by gaining two nods for higher-priced targeted therapies, for hypophosphatasia and lysosomal acid lipase deficiency.

MNCs Account For Majority Of Approvals

Putting lie to any lingering doubts that Japan is still "difficult" to access for non-Japanese companies, foreign multinationals dominated the approvals.

Even excluding any alliance deals under which a Japanese company was the approval holder for a licensed-in drug, a total of 23 new drug approvals (59% of the total) were granted to foreign companies last fiscal year.

The European industry led the pack, with Novartis AG securing approval of four products and Bayer Yakuhin Ltd. three.

New Drug/Diagnostics Approvals In Japan Fiscal 2015
Product	Indication	Company	Approval Date
Acoalan (antithrombin gamma)	Thrombophilia	Kyowa Hakko Kirin Co. Ltd.	July 3, 2015
Farydak (panobinostat)	Relapsed/refractory multiple myeloma (orphan)	Novartis	July 3, 2015
Ofev (nintedanib)	Idiopathic pulmonary fibrosis	Boehringer Ingelheim GMBH	July 3, 2015
Olanedine (olanexidine)	Skin antisepsis at surgical sites	Otsuka Pharmaceutical Co. Ltd.	July 3, 2015
Plaquenil (hydroxychloroquine)	Cutaneous/systemic lupus erythematosus	Sanofi	July 3, 2015
Strensiq (asfotase alfa	Hypophosphatasia (orphan)	Alexion	July 3, 2015
Trulicity (dulaglutide)	Type 2 diabetes	Eli Lilly & Co.	July 3, 2015
Xiaflex (collagenase)	Dupuytren's contracture	Asahi Kasei Pharma Corp.	July 3, 2015
Yervoy (ipilimumab)	Unresectable melanoma (orphan)	BMS	July 3, 2015
Caprelsa (vandetanib)	Unresectable medullary thyroid cancer (orphan)	AstraZeneca	Sept. 28, 2015
Copaxone (glatiramer)	Multiple sclerosis (orphan)	Takeda Pharmaceutical Co. Ltd.	Sept. 28, 2015
Effexor (venlafaxine)	Depression	Pfizer Inc.	Sept. 28, 2015
Marizev (omarigliptin)	Type 2 diabetes	MSD	Sept. 28, 2015
Miticure (house dust mite antigen)	House dust mite allergic rhinitis	Torii Pharmaceutical Co. Ltd.	Sept. 28, 2015
Mulpleta (lusutrombopag)	Thrombocytopenia in chronic liver disease	Shionogi	Sept. 28, 2015
Octreoscan (indium pentetoreotide)	Diagnosis of neuroendocrine tumors	Fujifilm RI Pharma	Sept. 28, 2015
P-Tol (sucroferric oxyhydroxide)	Hyperphosphatemia in chronic kidney disease patients on dialysis	Kissei Pharmaceutical Co. Ltd.	Sept. 28, 2015
Ventavis Inhalation (iloprost)	Pulmonary arterial hypertension	Bayer Yakuhin	Sept. 28, 2015
Viekirax (ombitasvir, paritaprevir and ritonavir)	Chronic hepatitis C, compensated cirrhosis (priority review)	AbbVie Inc.	Sept. 28, 2015
Yondelis (trabectedin)	Soft tissue sarcoma (orphan)	Taiho Pharmaceutical Co. Ltd.	Sept. 28, 2015
Zebiax (ozenoxacin)	Superficial skin infections/acne	Maruho Co. Ltd.	Sept. 28, 2015
Provocholine (methacholine)	Diagnosis of bronchial airway hyperresponsiveness	Sanwa Kagaku Kenkyusho Co. Ltd./Santen Pharmaceutical Co. Ltd.	Jan. 22, 2016
Repatha (evolocumab)	familial/normal hypercholesterolemia in high-risk patients	Amgen Astellas BioPharma KK	Jan. 22, 2016
Targretin (bexarotene)	Cutaneous T-cell lymphoma (orphan)	Minophagen Pharmaceutical Co. Ltd.	Jan. 22, 2016
Vaxem Hib (Haemophilus influenzae type B vaccine)	Prophylaxis of Haemophilus influenzae type B	Takeda	Jan. 22, 2016
Adynovate (rurioctocog alfa pegol)	Factor VIII deficiency	Baxter International Inc.	Mar. 28, 2016
Fycompa (perampanel)	Epilepsy (adjunctive use)	Eisai Co. Ltd.	Mar. 28, 2016
Imbruvica (ibrutinib)	Relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma	Janssen Pharmaceutical Cos.	Mar. 28, 2016
Kanuma (sebelipase alfa)	Lysosomal acid lipase deficiency (orphan)	Alexion	Mar. 28, 2016
Kovaltry (octocog beta)	Factor VIII deficiency	Bayer Yakuhin	Mar. 28, 2016
Mekinist (trametinib)	Unresectable melanoma with BRAF mutation (orphan)	Novartis	Mar. 28, 2016
Nucala (mepolizumab)	Intractable bronchial asthma	GlaxoSmithKline PLC	Mar. 28, 2016
Primaquine (primaquine)	Malaria	Sanofi	Mar. 28, 2016
Sabril (vigabatrin)	Infantile spasms (orphan)	Sanofi	Mar. 28, 2016
Sycrest (asenapine)	Schizophrenia	Meiji Seika Pharma Co. Ltd.	Mar. 28, 2016
Tafinlar (dabrafenib)	Unresectable melanoma with BRAF mutation (orphan)	Novartis	Mar. 28, 2016
Tagrisso (osimertinib)	Inoperable/recurrent EGFR T790M-positive non-small cell lung cancer	AstraZeneca	Mar. 28, 2016
Xofigo (radium 223)	Castration-resistant prostate cancer with bone metastases	Bayer Yakuhin	Mar. 28, 2016
Zykadia (ceritinib)	Unresectable advanced/relapsed ALK-positive non-small cell lung cancer	Novartis	Mar. 28, 2016
Source: PMDA. Approval holders only; licensing agreements not shown.

Shorter Delays

Product approvals in Japan are followed by a process for the granting of reimbursement under the country's national health insurance scheme, and new products can be commercially launched only once they are listed on the official tariff, which typically follows within a few months of approval.

While this adds to the time before patient access, ahead of this stage the PMDA has been steadily expanding its staff and introducing new systems to steadily bring down average approval review times. PMDA chief executive Tatsuya Kondo noted earlier this year that median approval times had fallen to 304 days in fiscal 2014.

Ongoing increases in review and other staff at the PMDA, pre-filing consultations, and harmonization moves enabling the wider acceptance of foreign data, have had a big impact in this effort. The Tokyo-based agency currently has around 850 staff and is aiming to increase the figure to around 1,000 by March 2019 (Also see "Japan PMDA To Kick Off New Asia Training Center" - Scrip, 17 Mar, 2016.).

Industry groups have applauded the improvements, with the US association Pharmaceutical Research and Manufacturers of America saying that it expects the average lag between US/EU and Japanese approvals to fall to around five months in the 2015-19 period, a fraction of the 42 months seen in 2006-09.

Another factor driving the changes is that the number of approval submissions is expected to more than double to a planned 363 in 2015-19, from 160 in 2006-09, PhRMA noted, with multinationals now routinely including Japanese sites in their international Phase III programs for new drugs. (Also see "Japan’s Crossroads: PhRMA’s Scangos Warns Of Policy Change Fallout" - Scrip, 13 Jun, 2016.)

Although it did not influence the fiscal 2015 figures, the PMDA introduced this April a new "Sakigake" system for the expedited approval of breakthrough therapies, which should help further bring down review and approval times. (Also see "Speedy review for pioneering drugs: understanding Japan's new Sakigake process" - Pink Sheet, 21 Apr, 2015.)

From the editors of PharmAsia News.