- 왜 접수거절(refuse-to-file, RTF)을 받았나?
- 대형제약사와 바이오텍
- 과학과 돈, 그리고 감옥
- 신약허가와 주가 (FDA와 SEC)
- Carl Icahn 그리고 주주 자본주의
- 애정과 배반 그리고 특허
- 인수와 합병
- 에필로그
1984년 설립되고 2008년 11월에 Eli Lilly의 100%로 자회사로 사라진 임클론은 미국 바이오텍 산업 -과학, 특허, 사업, 그리고 금융시장-의 다양한 모습을 알 수 있는 사례이다. 물론 다른 회사들도 좋은 사례이긴 하지만, 기업의 속속들이까지 노출되는 경우가 없는데, 다양한 이유로 해서 -주로 법정다툼들- 자료가 잘 정리된 회사이다.
바이오텍 산업은 눈에 보이지 않는 지식을 기반으로 하며, 그야 말로 규제의 바다를 항해해야 하고, 투자로부터 흑자전환까지 10년 이상 소요되어 – Vertex의 경우 20년 넘게 걸림- 자본시장에 극도로 의존하는 산업이다. 또한, 과학의 발달 정도로 본다면 물리학이나 고전적 화학이 이미 정립을 넘어 “Antique”해지는 단계라면 생물학은 이제 겨우 정체기를 벗어나 발전 속도에 탄력을 받은 정도이기 때문에 21세기에 가장 많은 Innovation이 나온다면 분명 바이오 분야일 것이라는 점에서 앞으로의 사업기회는 무궁무진한 산업이다.
이런 점에서 현재까지의 바이오텍의 속성을 잘 이해하고, 앞으로의 전망을 발전시키고 가다듬는(sharpening process) 과정을 반복하는데 있어 ImClone/Erbitux는 정말 살아있는 교과서역할을 할 수 있다.
1993년 LG화학(현재 LG생명과학)에 입사해서 그 당시 세계와 당당하게 경쟁하던 기상을 느끼며 직업생활을 시작한 필자도 어느덧 이 바닥에 20년이 넘은 중년이 되었다.
앞으로 20년 더 일한다면, 국내의 많은 과학자들이 임클론에 나오는 학자들, 사업가들 그리고 투자가들처럼 국제적인 인정을 받으면서 세계적인 영향력을 끼치는 사람들로 성장하길 희망한다.
그래서 20년 후 이런 종류의 글을 쓰면서 대전 전민동 WaBar가 전설의 장소로 기억 되고, 테헤란로의 카페들이 기라성같은 바이오텍들이 운명처럼 시작된 곳으로 추억되길 바란다. 판교에 수많은 바이오텍들이 탄생하고 성장하길 바라고, 많은 대학들과 병원들이 역사적인 약물들에 대한 아이디어와 과학적 실험결과들이 만들어지는 곳이 되길 소망한다. 그리고 그 과정에 최소한 “사업개발”의 분야와 바이오텍 사업전략의 분야에서 작으나마 역할을 할 수 있기를 소망한다.
연재를 마무리하며 참고할 만한 자료들을 정리해 본다. 아래 열거된 이외에도 구글링을 하면 더 좋은 자료들도 많을 것이다.
1. The Cell Game, Alex Prud’homme 저, HarperCollins e-books. 킨들버전도 있음. 임클론 초기부터 2002년 말까지의 이야기
2. Placebo or Panacea: The FDA’s Rejection of ImClone’s Erbitux Licensing Application
3. “Practical Lessons from a “Made for TV” Patent Litigation: The Trial of Yeda Research and Development Co. Ltd. v. ImClone System Inc. and Aventis Pharmaceuticals Inc.” , The Federal Law (Jan 2008)
4. 뉴욕주 지방법원 판결문. https://www.courtlistener.com/nysd/edxR/yeda-research-and-development-company-ltd-v-imclon/
5. 기타 주제별로 wikipedia 와 구글 검새을 통하여 자료 찾음.
그리고 임클론 관련하여 나름 정리한 연대기표를 첨부한다. 읽으시는 분들에게 조금이나마 도움이 되길….
1984 Joseph Schlessinger, Waterfield and Axel Ullrich(who discovered Her2 gene later published in Nature that mutated EGF R is erb-b.
1984 Late 1984 Ullrich presented the data on neu-2
1984 ImClone Founded [HQ Bridgewater, NJ, research HQ in NYC]
1985 Joseph Schlessinger went to Meloy Laboratories Inc. in Maryland for sabbatical position and made a couple of anti-EGFR mAb
1986 mAb-toxin conjugate concept conceived at Michael Sela’s lab [co-developer of Copaxane]
1987 Jan Schlessinger and researchers at Sela’s lab discussed about magic bullet concept
Schlessinger provided two mAb against EGFR to Sela’s lab
1987 Oct ImClone tried IPO in vain (due to market crash). Carl Icahn (Sam’s poker- and tennis-playing buddy) invested in ImClone
1988 March Schlessinger re-visited Weizman for seminar and received copies of results and a draft manuscript
1988 Ester Hurwitz and Michael Sela and co-workers published observations about synergistic effect of mixtures of mAb and cytotoxics at Journal of the National Cancer Institute. Sela primary author, Schlessinger one of the 6 authors
1988 Meloy sold to Rorer, and Rorer wanted to commercialize new drugs from Schlessinger’s research
1988 Sep Rhone-Poulenc Rorer filed 688 patent [Rhone-Poulenc Rorer 는 Rhone-Poulenc의 자회사로 1999년 Hoechst Marion Roussel과 합쳐져서 Aventis가 된다. HMR은 1995년 Hoechst AG, Roussel Uclaf, 그리고 Marion Merrel Dow의 합병에 의해 형성됨]
1991 Nov ImClone succeeded in IPO, raising $31.7m
1992 spring ImClone faced bankruptcy
1992 April Sam met Dr. Mendelsohn at a café on Manhattan [Chair of MSK Cancer Center’s department of medicine]
Licensed the patent from UC San Diego and converted into a chimeric mAb
1993 May ImClone raised $10.4m from the second offering [private placement]
1994 ImClone licensed 688 patent from Rhone-Poulenc Rorer
1994 ImClone tested several combinations with C225
1994 IND filing by ImClone
1994 Dec P1 started at Memorial Sloan Kettering, Yale Cancer Center, University of Virginia, and MD Anderson, University of Alabama
1995 March P1 SAD finished with 13 patients
1995 May 19 Dr. Mendelsohn presented the result at 35th ASCO in Atlanta
1996 Dr. Mendelsohn moved to MD Anderson Cancer Center as President
1997 Nov Shannon Kellum diagnosed colorectal cancer when she was 28.
1998 Shannon got surgery and several rounds of chemo with irinotecan, oxalipatin and Xeloda
1998 Merck KGaA lincesed C225 for European market at $60m
1998 May 4 NYT featured Dr. Judah Folkmann’s work [endostatin and XXX]
1999 March Shannon’s tumor growed too much and became refractory
Dr. Mark Rubin recommended C225 to Shannon
Shannon dosed with C225 for a month, once a week basis
1999 April Shannon’s cancer shranked by 50%
1999 Sep By the end of Sep., the C225/irinotecan shranked 80% of her tumors.
1999 Dec Shannon’s tumors shranked to resectable size and Dr. Rubin did surgery to remove them.
1999 ImClone started a new trial for colorectal cancer with Dr. Leonard Salt (Study 9923 trial)
1999 Aventis the merge between Rhone-Poulenc and Hoechst Marion Roussel
2000 Jan ImClone requested Dr. Sela for notebooks related to the 688 patents
2000 May Dr. Mendelsohn presented the interim data on 9923.
2000 May USA Today featured Shannon’s story
2000 May 22 Shannon appeared on ABC’s Good Morning for an interview.
2000 Aug 11 End-of-Phase II meeting at Woodmon I building in Rockville, Maryland
FDA: Susan Jerian, Patricia Keegan(Susan’s boss)
ImClone: Harlan Waksal, three RA experts, five oncologists including Lez Saltz
2001 Jan26 Fast-track status granted by FDA, [randomized C225 stand-alone study]
2001 March mid-March 27.94$ per share
2001 April 1 Enrolled a small group of patients for the single-agent study
2001 April 17 688 patent issued (Covering method of combining mAbs with chemotherapy drugs [US Patent No. 6,217,866]
2001 April Lehman Brothers (BMS) called Morgan Stanley(ImClone)
2001 May 3 Sam met Peter Ringrose, CSO, BMS
2001 May 12 P2 presentation at ASCO (in combo with irinotecan) 22.5% RR
[presented by Lez Saltz]
2001 June 1 Sam met Richard Lane,President of BMS’ WW Pharmaceutical Division
2001 June BMS’s due-diligence report warned.
2001 June Shannon testifies before Congress to emphasize the usefulness of compassionate use.
2001 June Early June $45.87
2001 June 20 Congress hearing on “compassionate use of investigational new drugs: is the current process effective?”
2001 June 20 Tender office price agreed to be $70 per share (70% premium)
2001 Sep 11
2001 Sep 19 deal signed and announced.
upfront $200m, NDA acceptance $300m, Approval $500m
39% royalty in North America
Manufacturing by ImClone
Co-development/commercialization in Japan on 50:50 basis
Stock $1b at $70 per share (75% market premium), 19.9%)
$14.4 m shares at $70 per share
Dec 7, 75.45 Dec21, 62.96 Jan 25 14.90
2001 Oct 12 Single-arm standalone (Erbitux only) with 57 patients
2001 Oct 29 ImClones shareholders participated in BMS tender offer
2001 Nov NDA filing
2001 Dec 7 $74.45 per share
2001 Dec 21 $62.96 per share
2001 Dec 26 ImClone founder Sam Waksal tells daughter to sell ImClone stock ahead of adverse FDA decision on Erbitux and tries to sell his own.
2001 Dec 27 Martha Stewart sells her ImClone shares. Prosecutors later allege she was tipped by her stockbroker that Waksal was trying to sell his.
2001 Dec 28, FDA rejected ImClone’s aNDA application
Protocol & reality차, documentation의실수 [CRO: PharmaNet]
Eligibility irinotecan refractory의기준, clinical operation에서실
2001 Dec Tamar Hawson joined BMS
2002 Early Yeda 866특허의 존재와 내용 파악하고 Aventis-ImClone과 협의 들어감.
2002 Jan BMS review of 9923 study [30.8% enrolled patients failed to meet at least of requirement of eligibility]
2002 March Revision of the licensing agreement with BMS with reduced future payment
2002 May Sam Waksal resigned, The company sued Sam
2002 June 12 Waksal arrested on insider trading charges
2002 July 13 Congressional committee holds hearing on ImClone scandal
2002 Oct 15 pleaded guily for securities fraud, bank fraud, obstruction of justice and perjury[위증]
2003 June 10 7년 3개월형. $4m
2003 Aug 14 Filing of NDA
2003 Oct Yeda filed suit against ImClone and Aventis with regard to 688 patent in Southern District of NY
2003 Oct 10 FDA’s acceptance of NDA
2004 Feb, 12 FDA approval for advanced CRC
2004 Sanofi-Aventis formed from merger between Sanofi-Synthelabo and Aventis
2004 July 16 Martha Stewart sentenced to five months in prison and five months of home confinement for lying about a stock sale
2005 Aug 30, Supplemental BLA for head and neck cancer
2006 March 1 FDA approves Erbitux for head and neck cancer, the first new treatment for those conditions in 45 years
2006 Aug 7 Stewart settes SEC’s civil insider trading charges involving her ImClone stock sale
2006 Aug 10 ImClone says it will remain independent, ending six-month search for a buyer. Invites shareholder Carl Icahn to join board
2006 Aug 23 ImClone nominates Icahn to board along with others he recommended. Icahn owns 13% of company
2006 Sep The court ruled over 688 patent [발명자가 Schlessinger와 동료들이 아니고 Sela의 동료[Sela, Pirak and Hurwitz]들임을 확인함]
2006 Oct 25 Carl Icahn acquired a majority, control of the board
2007 Jan Tamar Hawson left BMS
2007 Dec 7 ImClone settles drug patent dispute with Yeda regarding combo (866 patent)
$60 m each from Aventis and ImClone + royalties
2008 July 31 BMS offered take-over for $60 per share cash to Carl Icahn
2008 Sep 10 An undisclosed company offered $70 a share (DD due by Sep 28)
2008 Sep 23 BMS upped to $62 for acquisition
2008 Oct 6, $6.5b acquisition to Eli Lilly ($70/share)
2008 Nov 24 Became a fully owned subsidiary of Eli Lilly
2009 Feb 9 Released from BOP
2009 July FDA approved for the treatment of KRAS wild type colon cancer
2011 Nov 7 FDA approved for late-stage head and neck cancer