Bioventures: Growth strategies and importance for …...Bioventures: Growth strategies and...

Bioventures: Growth strategies and importance for innovation

日本の製薬企業の世界戦略としてのバイオベンチャー活用の道

ロバート・ケネラー (Robert Kneller, JD, MPH, MD）東京大学先端科学研究センター

www.kneller.asia [email protected]

12th Kitasato University - Harvard School of Public Health Symposium on Advanced and Global Drug Development :

Next steps for Japan to become a leading country in drug development 13 May 2013, Kitazato University, Tokyo

Outline of talk 講演概要

• Introduction and Background 背景 – Importance of new companies イノベーションのための新興企業（ベンチャー会社）の重要性 – Barriers to new companies in Japan 日本におけるベンチャー会社へのバリアー

• Strategy 1: Alliances with overseas partners • Strategy 2: Start companies in overseas to commercialize Japanese discoveries 戦略1:日本発の研究成果を商業化するために海外でベンチャー企業を設立する • Strategy 3: create independent, venture capital backed spin-offs to

commercialize dormant technologies – especially dormant industry-university joint discoveries

戦略2: 休眠中の技術を商業化するためにベンチャーキャピタルが支援するスピンオフ企業を設立する • Ways academia & government can promote growth of bioventures

2013/5/13 2 R Kneller, Kitazato-Harvard

Analysis of the origins of all 252 new drugs approved by FDA 1998-2007

Source: Kneller. 2010. Nature Reviews Drug Discovery 9 COLOR KEY

*Discovery usually means discover of the active therapeutic compound.

Discovery* in biotechs (new companies formed after 1975) or in universities followed by biotechs undertaking initial development, B + U>B. E.g: bevacizumab (Avastin, Genentech) & zanamivir (Relenza, Monash U > Biota), bortezomib (Velcade. ProScript), aglasidase (Fabrazyme, U Michigan > Coulter)

Discovery* in universities, and first development undertaken by a biotech in a different geographic region, U>Bout. E.g: adefovir (Hepsera) & tenofovir (Viread) (Czech Ac Sci & Catholic U Leuven > Gilead)

Discovery* in universities, and first development undertaken by a an established company (pharma), U>P. E.g: oxaliplatin (Eloxatin, Nagoya City U. > Tanaka Kikinzoku); cetuximab (Erbitux, UCSD & Weizmann Institute > Rorer)

Discovery* in a small established pharmaceutical company (all European, < 500 employees), Ps. E.g: , modafinil (Provigil, Lab. Lafon)

Discovery* in a large established pharmaceutical company, P. E.g: , pioglitazone (Actos, Takeda); capecitabine (Xeloda, Roche Japan)


FDA承認薬(1998-2007)の発見源 Kneller. 2010. Nature Reviews Drug Discovery 9から

COLOR KEY

*ここでの発明とは、治療活性化合物（active therapeutic compound）の発明とする。

バイオベンチャー(1975年以降の設立)によるもの、または大学の研究成果をバイオベンチャーが早期段階で開発したもの, B + U>B. E.g: bevacizumab (Avastin, Genentech) & zanamivir (Relenza, Monash U > Biota), bortezomib (Velcade. ProScript), aglasidase (Fabrazyme, U Michigan > Coulter)

大学の研究成果を他の地域のバイオベンチャーが早期段階で開発したもの, U>Bout. E.g: adefovir (Hepsera) & tenofovir (Viread) (Czech Ac Sci & Catholic U Leuven > Gilead)

大学の研究成果を大企業が早期段階で開発したもの, U>P. E.g: oxaliplatin (Eloxatin, Nagoya City U. > Tanaka Kikinzoku); cetuximab (Erbitux, UCSD & Weizmann Institute > Rorer)

製薬の中小企業(500人以下)で発明されたもの, Ps. E.g: , modafinil (Provigil, Lab. Lafon)

製薬の大企業で発明されたもの, P. E.g: , pioglitazone (Actos, Takeda); capecitabine (Xeloda, Roche Japan)


All drugs classified according to innovativeness by two methods FDA承認薬(1998-2007)の発見源を以下の2つの方法で再分類 1. Scientific novelty

科学的新規性

2. Health benefit 医療ニーズへの貢献

2013/5/13 R Kneller, Kitazato-Harvard 6

1. Scientific novelty 科学的新規性

Novel if either 新規性の定義

(a) new mechanism of action 新規の作用機序

or (b) first in a distinct class of compounds

医薬品クラスで初の化合物

If marketed within 3 years of first-marketed drug in Japan, Europe or US, still qualifies as novel.


2. Health benefit 医療ニーズへの貢献

Classification relies on whether FDA granted priority or standard review of New Drug Applications (NDAs) in the case of new molecular entities (NMEs, small molecule drugs). • Priority review 優先審査 (to be completed in < 6 months)

for drugs that offer “substantial benefit over currently marketed therapeutics” (designated by p in charts).

• Standard review 標準審査 (in principle, < 12 months) for other NMEs (designated by s in charts).

• Drugs reviewed under Biologic License Applications (BLAs) 生物製剤承認申請の枠で審査されたもの were analyzed separately, because before 2004, priority or standard review status was often not recorded for biologics (designated as b in charts). Biologics analyzed separately as one group.


Same patterns even if classify on basis of peak world wide sales rather than number of drugs 薬剤の数ではなく、売上ピーク年の売上高で再分類しても、このパターンは変わらない。

• However, biologics account for the high peak sales of biotech and university > biotech drugs.

• Sales of university > biotech small molecule drugs tend to be low. (Many are orphan drugs.)


Bioventures also play an important role taking drugs through regulatory approval and market launch. バイオベンチャーは、薬品の発見だけではなく、FDA承認を経て、市場に出回るまで、重要な役割を担う。


Startups are especially suited to carry out initial development of university discoveries. 大学における研究成果の早期段階における開発にはベンチャー企業が適していることが多い

• Hardly any innovative drugs discovered in universities anywhere in the world were initially developed by major pharmaceutical companies.

世界中の主要な製薬会社が、大学等の研究機関で発見された科学的に目新しい薬剤の初期開発を請け負うことはめったにない。

• Overall, startups are much more likely to discover innovative drugs or to undertake the initial development of innovative university drugs, than are established companies.

製薬分野においては、ベンチャー企業が既存の大手企業に比べ、新薬を生み出す可能性が高いことが論拠を持って示されている。


Weaknesses in Japan’s entrepreneurial ecosystem 日本の起業家生成システムの弱点

1. Human resources locked up in old organizations 人材は、古い組織の中に閉じ込められている

2. Tendency to focus mainly on domestic market and alliances 国内市場やアライアンスに集中する傾向

a. Language barrier inhibits global networking by entrepreneurs グローバルネットワークを阻害する言葉の壁

3. Limited access to capital 資金へのアクセスが制限されている

4. Autarkic (self-reliant) innovation strategy in large companies 大企業の自前主義

a. Conservative, risk averse strategy in dealing with outside companies b. Prefer to hoard unused technologies rather than to license or to form spin-offs. 研究開発成果の死蔵が頻繁である

5. Pre-emption of university researchers’ discoveries & time by large companies 大企業は大学における研究成果などを先買する。

6. No small businesses preference in government procurement, and Japan equivalent to the US SBIR program is cumbersome. アメリカの連邦政府調達（元請け・下請け合計）の最低20％が中小企業からでなくてはならない。同様の規制は、日本には存在しません。

7. Hesitancy to build disruptive companies that will take market share from existing companies 既存の企業から市場シェアを奪う企業を構築することへの躊躇


Current approaches to the “dry pipeline” problem in Japan

枯渇したパイプラインへの現行アプローチ

• Startups (bioventures) rarely mentioned. スタートアップ企業は言及されない。

• Instead, “Partner with Universities!” 大学との連携の強調

• tocilizumab (Actemra®, Chugai & Osaka U.) often cited as a prototype for successful collaboration.

• Also nicorandil (Nitorubin®,Chugai & U. Tokyo)


But there are cases where pharmas were slow to develop university drugs

製薬会社の対応が遅かった薬品の例

• oxaliplatin (Eloxatin, from Nagoya City University) eventually developed by DebioPharma

• Although Novartis successfully developed imatinib (Gleevec), Brian Druker of Harvard and Oregon HSU had to push Novartis hard to start.

• The above study cautions against undue optimism that collaboration with universities will result in many innovative drugs reaching market. – U>P drugs generally were no more innovative than average.

• Alignment of interests better for university <-> bioventure <-> pharm than for university <-> pharma.


What to do?

• Give up on Japanese bioventures, continue to rely on in house research, collaborations with universities, and buy-outs of foreign biotechs? 日本のバイオベンチャーに頼る

のはあきらめ、自前の研究に頼り、大学との連携を強め、海外のバイオベンチャーを買収してはどうか。 – Too risky. リスクが高すぎる。

• Try different strategies to increase the likelihood that entrepreneurial innovation will succeed and Japanese pharmas can take advantage of this success. スタートアッ

プ企業によるイノベーションの可能性を高め、日本の製薬企業がその成功の恩恵を被るような戦略に振り替えるのはどうか。


Strategy 1

Start a bioventure in Japan. Grow quickly by aiming for international alliances and markets.

Examples: a. PeptiDream: breakthrough and largest

contracts with overseas pharmas. b. Oncolys Biopharm: $300 M license to BMS to

develop festinavir for HIV drug, jointly discovered by researchers at Showa, Kagoshima and Yale Universities.


Strategy 2: Start company (or branch company) in

America to commercialize Japanese discoveries

戦略2: 日本発の研究成果を商業化するために海外のベンチャー企業、又は枝会社、を

設立する


Example 例 2a: Acucela

• Started in Seattle by Dr. Ryo Kubota (from Keio U.) to develop drugs for eye diseases.

• Lead compound, ACU-4429, for dry age-related macular degeneration (AMD) in phase 2b/3 trials in US – Trials funded by partnership with Otsuka

• Illustrates virtuous cycle: – Japanese invention ⇒ development overseas by entrepreneurial

start-up ⇒ technology brought back to Japan by license or M&A • Advantages of US:

– Easier to recruit skilled people, particularly with regulatory expertise

– Easier environment for clinical trials • Recruitment of patients & study sites, networking, FDA consultations,

etc.


Examples 例 2b: Regimmune

• Immune system modulation therapy (induction of regulatory T cells by α-GalCer) from Riken (Dr. Yasuyuki Ishii)

• Phase I/II trial in US to prevent graft vs. host disease in bone marrow transplant patients – Other applications: type 1 diabetes, other autoimmune

diseases such as rheumatoid arthritis, allergies • Headquarters in Tokyo, but has had laboratory in Silicon

Valley, first to conduct pre-clinical trials, now to manage clinical trials.

• Advantages of US: similar to those cited by Acucela


Example 例 2c: Seiko Wave

• High speed, real time, large or small scale, precise 3D imaging (using visual light)

• Combines Japanese optical and US software expertise o particularly from University of Kentucky

• Applications in dentistry, sports training, lung function testing, etc.

• Twin companies, one in Japan, one in US


Strategy 3: create independent, venture capital

backed spin-offs from large companies to commercialize dormant technologies

戦略3: 大企業で休眠中の技術を商業化するために

ベンチャーキャピタルが支援するスピンオフ企業を設立する


Advantages 利点

• Technologies would be closer to POC and have some industry validation

“概念実証” に近く、産業界も有効性を認めた技術がある。

– Investors would prefer this option 投資家はこの種のベンチャー企業を好む。

• This strategy would be ideal in the case of a promising joint university-company discovery, that does not fit within the Japanese parent’s business strategy.

共同研究から、日本企業の事業戦略にあわず、商業化の見込みがないような成果が出た場合に理想的なオプションである。

– Rather than abandoning the project, it might find investors who are willing to take the risk to aim for a commercial hit.

共同研究の成果を棚上げにして放置しておくよりも、リスクを取ってでも、ヒット商品を狙う資家につなぐ方が「だれにとっても有益なシナリオ」である。


Example 例 3a: Prism Pharma

• Dr. Hiroyuki Kouji 小路弘行 developed compounds to modulate intracellular protein interactions while working at Asahi Kasei

• In 2006 left Asahi Kasei to found Prism BioLab • Lead drug is PRI-724, a CBP/Catenin inhibitor, that

signals cancer cells to differentiate rather than proliferate.

• Phase 1 trials began in USA in 2011. • Shortly thereafter, Prism signed $300M licensing

deal with Eisai


Example 例 3b: Medicinova

• Founded 2000 in San Diego by Dr. Yuichi Iwaki (Sapporo Medical School ⇒ Professor Univ.

Southern California Medical School)

• Has pipeline of 7 drugs candidates, almost all in-licensed from Japanese companies such as Kissei, Kyorin and Mitsubishi Pharma. – Two leading drugs are in phase 2 trials in the US


Example 例 3c: TeraView • Developing applications for terahertz spectrum light (between

infrared and microwave). • Seeds of this technology arose from research between

Toshiba Research Europe (TRE) and Cambridge Cavendish Laboratory (CCL)

• Potential applications in many areas including – dentistry & medicine – quality control for pharmaceuticals & semiconductors

• Toshiba decided it did not want to develop • CCL scientists wanted to start a company and found venture

capital investors • Working through IP issues was tricky • Founded 2001. • Now with 50 employees and growing. • Toshiba is a shareholder, but does not try to control decisions.


Ways academia & government can promote bioventure growth


I. Problem: Scarce support for translational research

• Example: New rheumatoid arthritis drug target identified, but no funding or personnel to carry research beyond early stage mouse studies.

• Example: New insulin sensing and release system that is completely within the body, but no funding for mouse studies.

• In contrast, most leading American universities have set up funds for proof of concept research (~$50,000 for two years).

• Nationwide, America has NIH and Coulter grants for translational research.


Suggestions for translational research funding

• Develop national and local (e.g., single university) programs.

• Fund large numbers of small projects • Review applications on a rolling basis (not just

once a year). • Non-bureaucratic

– Administration and evaluation should be done at local level.


II. “Wise” financing for startups

• The 文科省 (MEXT) START program (government co-funding with private venture capital) is a promising initiative (see http://www.jst.go.jp/vc/event/20121022/hokoku.pdf)

• What about government loans? • Avoid creating “dependent,” “virtual” or

“hobby” startups. • De-emphasize large consortium projects

• Patent pooling among consortium members generally is not helpful for startups.


http://www.jst.go.jp/vc/event/20121022/hokoku.pdf

III. Co-funding for clinical trials

• Many bioventures seem to have NEDO funding – 2/3rds NEDO, 1/3rd private co-funding seems

generous. – However, trials have to be in Japan

• Don’t discourage overseas trials – Maybe allow some government co-funding for

overseas trials – Especially considering that profits from overseas sales

will probably be much higher than from Japan sales • Government loans?


IV. Other regulatory issues

• PMDA seems to have made great progress in harmonization – Relatively few complaints about overseas clinical

data not being accepted by PMDA – Patient accrual, expense, approval delays are still

problems

• Japan’s flexible policies for compassionate need, 医者臨床試験 trials is helpful for bioventures.


V. Encourage investment from overseas

• Harmonization of corporate governance rules • Avoid double taxation when an IPO or buy-out

occurs.


Thank you for your attention and comments. ご清聴ありがとうございました。コメントや感想を歓迎いたします。


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