Pharma Power Japan Barely In COVID Vaccines Race. Why?
Long-Standing Lag In New Spotlight
Executive Summary
Despite having multiple world-class pharma companies and innovative research, Japan is notably absent as a source of candidate vaccines for the coronavirus. The pandemic is again throwing into sharp relief past and present challenges around the country's vaccines sector.
Japan has one of the largest single-country pharma markets in the world, a handful of major R&D-based companies with multiple innovative drugs sold around the globe, and a record of innovation that stretches back decades and includes multiple blockbusters.
So why, as the first approvals for other developers start to come through globally, is the country barely moving the needle when it comes to coronavirus vaccine activity?
The answers are multiple and complex.
First of all a quick snapshot of where the supply situation stands. Of the nearly 120 vaccines against COVID-19 which Biomedtracker shows are currently in global development, only one from Japan is at present among the just over 50 already in the clinic.
If it were relying solely on domestically developed and manufactured candidates to protect its citizens, it would probably be well into 2022 until the country’s first inoculations become available, and then only in limited quantities.
Correctly judging this is unacceptable to the majority of the public wanting their lives to get back to normal – and probably with an eye on moving ahead with the delayed Olympics next year - the national government has turned instead to the now well-known major international developers. Pfizer Inc./BioNTech SE, AstraZeneca PLC/University of Oxford and Moderna, Inc. have already contracted to supply doses sufficient to cover Japan’s 126 million population.
The first two have signed up for a total of 240 million doses, while Japan’s leading pharma firm Takeda Pharmaceutical Co. Ltd. – which itself has long-standing vaccine experience - will distribute 50 million doses of Moderna’s mRNA vaccine mRNA-1273, starting in the first half of 2021, with the US firm to make the finished product.
It currently looks like doses of the Pfizer/BioNTech vaccine BNT162b2 for 60 million people will be supplied by the end of next June, helped by results from a 160-patient confirmatory trial being run by Pfizer in Japan. AZ started back in August a similar 250-patient local trial to support its candidate.
That same month, Takeda also reached an alliance with Novavax, Inc. for the clinical development, manufacturing and commercialization in Japan of NVX-CoV2373, Novavax’s COVID-19 vaccine candidate, with funding from the Ministry of Health, Labour and Welfare. The aim is to build capacity for over 250 million doses of the vaccine per year.
Another major Japanese firm that has long been present in the sector, Daiichi Sankyo Co., Ltd., began discussions with AZ in June for the “stable supply” in Japan of the UK firm’s recombinant adenovirus vector vaccine AZD1222. Its Daiichi Sankyo Biotech subsidiary intends to formulate the product for Japan, using its existing flu vaccine facilities.
In all, Japan has set aside a total of JPY671.4bn ($6.44bn) in an extraordinary budget for its coronavirus vaccine supply program, and under a special bill passed in late October revising the existing vaccines law, the jabs will be made available at no out-of-pocket cost to all recipients, with the usual prioritizations.
In echoes of the country’s past experiences with vaccines, the government has also agreed to indemnify suppliers from having to pay compensation from any adverse effects proven to be related to the vaccines.
Anges Leads A Small Pack
So, there may be plenty of activity around securing supplies, but this exclusively relies on foreign originators.
Leading the modest R&D efforts underway at home is mid-sized biotech Anges, Inc., which joined the development fray early after the pandemic took hold but only just started in early December a 500-patient Japanese Phase II/III trial with its plasmid DNA-based candidate, currently expected to be completed next March.
The company is partnering with Osaka University and Japanese biotech group Takara Bio Inc., along with Brickell Biotech, Inc. of the US, but a larger Phase III trial is expected to start only next year, with Anges saying recently it will probably have to include other Asian sites given a likely lack of enrollees at home. The first late-stage data will probably not emerge until calendar Q3 of next year.
The other R&D players include Daiichi Sankyo, which has said it prioritizing work on a prototype mRNA vaccine DS-5670 in an alliance with the University of Tokyo and the Japan Agency for Medical Research and Development (AMED), making use of the company’s proprietary nucleic acid delivery technology. In this case, the current expectation is to move into clinical studies in Japan around March 2021.
Shionogi & Co. Ltd. has also said it is moving ahead with the development of potential coronavirus vaccines and is working with acquired Japanese vaccines venture
UMN Pharma, Inc. on an rDNA candidate using a baculovirus expression vector system. This is currently expected to emerge with supporting clinical data in the first half of next year.
The only other runner appears to be Meiji Holdings’ KM Biologics operation, which has said it has started work on an inactivated vaccine with several partners, including the National Institute of Infectious Diseases, and plans to launch large trials around next spring. KM took over certain pharma operations of Japan’s Chemo-Sero-Therapeutic Research Institute (Kaketsuken) and has been focusing on flu vaccines.
Takeda, which has a long-standing presence in basic vaccines in Japan, does now see novel vaccines as a business pillar and is nearing the first filings for its novel dengue candidate TAK-003. It is also working with Zydus Cadila on a chikungunya vaccine and given the Indian firm has completed Phase II dosing for its own DNA COVID-19 vaccine, any expansion of this alliance is also being watched.
Helping, Hindering
It is therefore clear that, while there is some R&D activity going on in Japan, the original research (as opposed to supply alliances) remains very limited in scale and is occurring on timelines well behind those of both the major western developers and the multiple Chinese firms already forging ahead with final-stage trials.
One limiting factor has certainly been trial recruitment challenges due to the relative lack of COVID-19 patients in Japan - something cited both by Anges in deciding to expand its Phase III program outside the country and by Fujifilm in the delays of local trials with its antiviral favipiravir earlier this year.
(There had been around 179,900 reported SARS-CoV-2 cases in Japan as of mid-December, and the per capita infections and death rates remain lower than many other major countries.)
But set against this, there are very few hurdles on the regulatory side, as Japan’s drugs regulator, the PMDA, the health ministry and AMED have all been publicly and highly supportive of research. Concrete evidence of this came in the expedited approval given earlier this year to Gilead Sciences, Inc.’s antiviral remdesivir, which was reviewed and cleared in a matter of days.
Other state funding (besides for the big supply deals) has also been readily available and used to support technology transfers, establish cold chain infrastructure and scale-up manufacturing capabilities.
A deeper look reveals long-standing historical and policy factors that have hampered Japan’s overall capacity for developing and commercializing innovative vaccines, and which are again showing up amid the pandemic.
Critics have long seen the country’s smaller domestic manufacturers as being protected from competition by the government’s reluctance to pursue imports of basic vaccines, enabling them effectively to rely on regular supplies of older products to national immunization programs. This in turn can be said to have stunted the development of innovative platform technology.
There have been attempts to form new entities, notably the 2012 agreement between GlaxoSmithKline plc and Daiichi Sankyo to form the Japan Vaccine Co. Ltd. joint venture. But this was dissolved around two years ago and its commercial activities moved back to the respective companies in April 2019, in light of what the partners said were “changes in the Japan vaccine business situation.”
Mind The Gap
Meanwhile, the national program itself, first developed post-war in the late 1940s, has long been seen as comprising a much more limited range of vaccines versus other developed countries - again effectively limiting the development of general capabilities and capacity in the national vaccines sector.
Haemophilus influenzae type B (Hib) vaccines, for example, began to be routinely made available in Japan as late as 2008, and then only after a long battle faced by Sanofi Pasteur as the first foreign vaccine supplier in the country, and with the products available initially only on the private (self-pay) market.
Despite some improvements in the scope of available and reimbursed vaccines in the years since, the “vaccine gap” in Japan, as illustrated by the Hib case, and challenges in securing reimbursement under the National Health Insurance scheme, continue to be long-standing concerns for the big multinational vaccines producers.
An apparent policy de-emphasis within the government of vaccines in general also seems to have been related to a number of successful and high-profile public lawsuits brought against the state in the 1990s, over claimed side-effects from MMR (measles, mumps and rubella) vaccines.
In addition, compensation claims related to Japan’s high rate of hepatitis infections - attributed in part to the re-use of needles in post-war mass vaccination campaigns – provides another background factor.
Considering this history, perhaps it’s not surprising that government policy and administrative support in recent years has pivoted much more towards regenerative medicine and cell therapies, notably those related to induced pluripotent stem (iPS) cells following the Nobel Prize win in 2012 by pioneer Shinya Yamanaka.
Lingering Hesitancy?
Besides these factors influencing the development and capabilities of the industry – and as now reflected in the current state of play on coronavirus vaccines - other historical factors may be behind the Japanese public’s sometime skeptical views on, and willingness to receive, vaccines in general.
A 1994 revision to the Preventative Vaccine Law made many jabs voluntary rather than compulsory, meaning that younger generations may have become less familiar with the concept of inoculation than their parents.
The many parents who have experienced the complicated, multi-dose and multi-visit schedule required for the inoculations required by law for newborns under the age of one may have been put off in general, especially as catch-ups outside this schedule must be paid out-of-pocket. (One reason for the demanding schedule was the lack of combination vaccines common elsewhere.)
Relatively recently, in 2013, there were other high-profile cases, covered extensively in the national mass media, of unexplained side-effects recipients and their families said were linked to the administration of the then new to Japan human papillomavirus vaccines Cervarix (from GSK) and Gardasil (Merck & Co., Inc.).
The general pain syndrome was investigated by the PMDA, which said it was of unclear pathogenesis but that a link with the vaccines could not be ruled out. What is clear is that the cases did nothing to reassure an already cautious public.
Whether these hesitancy factors will play out for the new COVID-19 vaccines, despite the promised zero out-of-pocket cost, remains to be seen.