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Special Problems of Early Testing in Humans of Innovative Drugs Acting on the Central Nervous System

Special Problems of Early Testing in Humans of Innovative Drugs Acting on the Central Nervous System : 작성자, 카테고리, 작성일, 조회수, 원문,출처, 정보 제공
작성자 관리자 카테고리 전문가 인사이트
작성일 2016-05-04 조회수 1,488
원문
출처

Special Problems of Early Testing in Humans of Innovative Drugs Acting on the Central Nervous System or the Immune System

전문가
글 Werner Krause, Ph.D.
GPKOL위원
소속 및 직위 (Company Name& Position)
  • VivoTecc GmbH
    Königin-Luise-Str. 27
    14195 Berlin
    Germany
    CEO
    w.krause@vivotecc.com
학력사항
  • 1976 University of Erlangen, Germany / Chemistry (Ph.D.)
경력사항
  • 2015-현재 VivoTecc GmbH, Germany, CEO / Co-Founder
  • 2009-2014 Bayer Healthcare, Germany, Global Project Manager
  • 1999-2009 Schering AG, Global Program Manager
세부 전문분야 및 컨설팅 내용
  • Clinical Trial

요약 (Abstract)

This article presents three examples of Phase I studies covering drugs that either affect the central nervous system (CNS) or the immune system and that resulted in clear-cut disasters (two cases) or in at least big surprises due to an unforeseeable chain of events. The objective is to draw conclusions (Lessons Learned) in order to prevent similar outcomes in future Phase I studies.

BIA 10-2474 is a fatty acid amide hydrolase (FAAH) inhibitor developed by Bial-Portela, Coronado, Portugal and was examined in a Phase I study comprising four parts, single oral dose ascending, fed vs. fasting conditions, multiple oral dose ascending, and pharmacodynamics. In the third part of the study, one volunteer fell ill with stroke-like symptoms after the fifth dose of 50 mg and died one week later. Four subjects were hospitalized with similar side effects after six doses of 50 mg whereas one volunteer did not experience any side effects after six daily doses of 50 mg.

TGN1412 is a humanized monoclonal antibody binding at the CD28 receptor, a so-called “superagonist” and was developed by TeGenero Immuno Therapeutics, Würzburg, Germany. The first six subjects that were injected with the lowest dose of 0.1 mg/kg at intervals of 10 min experienced severe side effects due to a cytokine storm. Permanent damage could not be excluded.

FG7142, a small molecule, which was isolated from human urine, was originally supposed to be the “endogenous benzodiazepine” and to exhibit anxiolytic efficacy, was studied by Schering AG, Berlin, Germany in a Phase I trial. Higher doses all of a sudden resulted in severe anxiety.

The outcomes of all three Phase I studies were evaluated based on publicly available data. Conclusions drawn from the events therefore have to be considered as personal opinion with the disclaimer that knowledge of all data might lead to a different result.

목차(Table of Contents)

1. Introduction

2. Main Subject

  1. General Remarks
  2. BIA 10-2474
  3. TGN1412
  4. FG7142

3. Summary and Recommendations

Ⅰ. 서론(Introduction)

Phase I studies are the first chance to obtain an idea of the safety and tolerability – and in some cases also of the efficacy – of a new drug following extensive preclinical investigations. The hurdles that have to be passed before starting these studies are very high and they are clearly defined by regulatory authorities and by international declarations, e.g. on ethical issues, such as the Declaration of Helsinki. There is general agreement that a Phase I study should be safe for the participants if all checkpoints have been passed.
In this article I will present three examples of Phase I studies in the fields of the CNS or the immune system that did pass all controls and nevertheless ended in disaster or in big surprise. These examples will be used as the basis for Lessons Learned in order to further fine-tune the prerequisites that have to be fulfilled either before starting a Phase I trial or during the study.
The caveat and disclaimer for my conclusions and recommendations, however, are that I could only use publicly available information, which might or might not reflect the real status of the data.

Ⅱ. 본론(Main Subject)

2. BIA 10-2474
BIA 10-2474 has been published as a reversible fatty acid amide hydrolase (FAAH) inhibitor [1, 2] and was developed by Bial-Portero, Coronado, Portugal. It is a small molecule with the chemical structure illustrated in Fig. 1. The drug is supposed to increase the levels of the neurotransmitter anandamide, which acts on endocannabinoid receptors in the CNS, both centrally and peripherally. Potential indications for BIA 10-2474 that had been taken into consideration were anxiety, Parkinson’s disease, chronic pain, multiple sclerosis, cancer, hypertension, and obesity [3, 4].
Preclinical drug development started in 2009. Mouse formalin-paw and tail-flick tests showed analgesic/anti-inflammatory activity [5]. The drug was available labeled with radioactive 14C. The half-life of 14C-labeled compounds in the plasma of rats was 45 h after oral administration and 4 h after intravenous dosing indicating significant differences in the pharmacokinetics (PK) after oral and intravenous dosing. In dogs, half-lives of 104 h orally and 52 h after intravenous injection were reported pointing in the same direction of PK differences. Data on the pharmacokinetics of the unchanged drug, on oral bioavailability or on biotransformation are not publicly available.
Repeated dose toxicity studies for 13 weeks were performed in mice, dogs, and monkeys and for 26 weeks in rats. Only few adverse events were reported in any of these studies. The oral no observed adverse level (NOAEL) varied from 10 mg/kg/d in rats to 75 mg/kg/d in monkeys. No significant CNS effects were observed in safety pharmacology studies up to doses of 300 mg/kg/d. The proposed human equivalent to the 26-weeks NOAEL in rats was 100 mg. No data were publicly available on receptor occupancy, in vivo ligand binding saturation levels, measures of target affinity or assessment of non-target binding interactions.
The Phase I study was approved by the French regulatory authority, Agence National de Sécurité du Medicament et des Produits de Santé (ANSM), on June 26, 2015 and by the regional Ethics Committee on July 3, 2013. It started in Rennes, France, on July 9, 2015 and was performed by the CRO, Biotrial. The study title was “A double-blind, randomized, placebo-controlled, combined single and multiple ascending dose study including food interaction, to investigate the safety, tolerability, pharmacokinetic and pharmacodynamic profile of BIA 10-2474, in healthy volunteers” [5]. The study had an adaptive design and comprised four parts:
  • Single oral dose ascending, double-blind, 0.25, 1.25, 2.5, 5.0, 10, 20, 40 and 100 mg, N=8 per dose level (3:1 randomized)
  • Fed vs. fasting conditions (40 mg, N=12), cross-over, double-blind
  • Multiple oral dose ascending (10 daily doses, N=8/dose, 2.5, 5.0, 10, 20 and 50 mg), double-blind (3:1 randomized)
  • Pharmacodynamics vs. placebo with different challenge agents, open label, N=20, male only, cross-over
128 male or female volunteers were recruited into the study, their age was 18-55 years. They received €1.900 compensation for their participation. The study drug comprised capsules of 0.25, 2.5, and 10 mg of drug. Overall, the design of the study was state of the art.
Everything proceeded well in the trial until the 50-mg dose of the multiple ascending dose level part was reached. The previously administered 2.5 – 20 mg per day for ten days was tolerated by all subjects without any problems. The first subject fell ill with stroke-like symptoms on the evening of the 5th dosing day (January 10, 2016) and died on January 17, 2016. Dosing of the remaining subjects continued on January 11 but was stopped on the same day. Four of the five volunteers were hospitalized with similar symptoms including deep brain hemorrhage and necrotic lesions, potentially leading to irreversible damage. One subject did not show adverse effects. All subjects were released from hospital by January 21, 2016.
The disaster in Rennes was made public on January 15, 2016 [1, 6, 7] and received wide-spread echoes worldwide [8-10]. On February 5, 2016, the French authority, Inspection Générale des Affaires Sociales (IGAS) commented on the outcome of the study as follows [11]:
  • No study stop when the first subject was hospitalized, five volunteers continued to receive drug
  • No immediate reporting of the incident but only four days later
  • No re-consenting of the remaining subjects after the first incident
The French Health Minister additionally commented that some of the protocol provisions were too vague and that the inclusion criteria (on other substance use) were not explicit enough [12]. Other drug companies that had FAAH inhibitors in their portfolios (Table 1) immediately stopped any ongoing trials [13]. Some of them had already abandoned the FAAH approach earlier, due to lack of efficacy.
ANSM established an Expert Committee consisting of toxicologists, pharmacologists, and neurologists to review all available data on BIA 10-2474 and other FAAH inhibitors. The Committee announced in its preliminary report of February 2016 [14] that the observed brain effects were probably due to the mechanism of the drug and the high dose. They also announced that several monkeys died or had to be euthanized during the toxicology studies and two dogs due to lung injuries after the highest dose level in the 13-week study. These results had not been disclosed previously.
My personal opinion on the tragic results of the Phase I study is that the following information would be helpful but is not (publicly) available in order to fully evaluate the reasons for the adverse effects:
  • Bioavailability in the animal species used in toxicology studies
  • Pharmacokinetics (plasma levels, half-life, bioavailability, dose linearity, inter-individual variability) in humans
  • Is there drug accumulation after repeated dosing?
  • Biotransformation pathways, in particular which enzyme systems are responsible (animals/humans)?
  • Is there induction/inhibition of enzyme systems such as CYP3A4, CYP2D6, etc.?
  • Are there geno- or phenotypically slow and fast metabolizers regarding any of these enzyme systems?
  • Are there toxic metabolites (of drug or anandamide) in humans, not present in animals?
  • On-target receptor binding (IC50, central vs. peripheral binding)
  • Off-target receptor binding and enzyme inhibition
  • Reversibility of receptor binding
  • Purity of the administered drug
From the available data, one could come to the conclusion that the pharmacokinetics of BIA 10-2474 is non-linear, with non-linearity starting between 20 and 50 mg, potentially due to saturation or inhibition of enzymes that metabolize and inactivate the drug. As a consequence, drug accumulation might have occurred upon multiple dosing. Additionally, judging from the one subject in the 50-mg group that did not experience any side effects, one might conclude that there are geno- or phenotypic differences in these enzyme systems leading to the existence of slow and fast metabolizers. The one volunteer that tolerated the 50-mg dose potentially was a fast metabolizer and the others were slow metabolizers, in particular the one subject that died, or intermediate metabolizers.
It seems particularly tragic that such high doses were included in the study in spite of the conclusion made later by the Expert Committee that, based on the company's IC50 data, complete FAAH inhibition should have been achievable already with a dose of 1.25 mg in humans.
However, without full knowledge of all available data, my conclusions might be considered mere speculation.
3. TGN1412
TGN1412 is a genetically engineered and recombinantly expressed humanized monoclonal antibody (IgG4- type) of murine origin, binding at the C”D loop of the CD28 receptor on T lymphocytes as a strong agonist, a so-called “super-agonist” since it does not need co-stimulation for its effect [15]. It was developed by TeGenero, Immuno Therapeutics, Würzburg, Germany. The proposed mechanism of action is expansion and activation of T cells without pro-inflammatory reactions. In animal studies, anti-CD 28 antibodies orthologous to TGN1412 had anti-inflammatory properties triggering an increase in T-cells, with regulatory T-cells multiplying fastest and taking control. The regulatory T-cells calmed the immune system. This was the effect that TeGenero built its hope on in developing the drug assuming that symptoms of diseases like rheumatoid arthritis, where normal T-cells attack the body’s own tissues, could be reduced or abolished. Proposed indications therefore included rheumatoid arthritis and B cell chronic lymphocytic leukemia (CLL).
In ex vivo experiments using primary blood samples from B-CLL patients, TGN1412 induced a profound polyclonal expansion and activation of T cells as judged from the expression of activation markers such as CD25, CD69, CD40L, and CD134. Apoptosis of leukemic B cells was induced via CD95 and TRAIL pathways after co-culture with TGN1412 [16].
Preclinical evidence from multiple animal models inlcuding monkeys suggested that TGN1412 had the potential to significantly benefit rheumatoid arthritis patients by the induction of anti-inflammatory cytokines, expansion of regulatory T cells and other mechanisms [16]. Since CD28 is restricted to humans and non-human primates, safety and toxicology studies were mainly performed in these species. In single- and multiple-dose studies, TGN1412 was well tolerated without any signs of toxicity, hypersensitivy or systemic immune system deviations up to doses of 50 mg/kg/week for four weeks. Local tolerance studies with intravenous, perivenous, or intra-arterial administration did not produce clinically significant irritation. Likewise, preclinical pharmacology studies showed a predictable, well-defined pharmacokinetic profile after infusion of 5-50 mg/kg. Maximum plasma levels (Cmax) and areas under the plasma level-time curve (AUC) were largely proportional to dose.
On March 13, 2006 the CRO, Parexel, initiated a Phase I study in London. The protocol had been approved by the British health authority, MHRA. Drug administration to the first six patients should be performed from 8 – 10 am. The design of the study was as follows:
  • Double-blind, randomized, placebo-controlled, N=6 on drug, N=2 on placebo
  • Subjects: Male, 19-34 years (median 29.5)
  • Doses: 0.1, 0.5, 2.0, and 5.0 mg/kg
  • Starting dose: 0.1 mg/kg = 1/500 of the highest dose used in cynomolgus monkeys (which was safe)
  • IV infusion over 3-6 min, starting at 8 am, interval of 10 min between patients
  • Each subject received a fee of £2,000
Approx. 5 min after the last infusion of the lowest dose of 0.1 mg/kg, the first subject complained about headache, fever, pain and a feeling of “burning”. Shortly thereafter the remaining subjects on drug experienced the same symptoms including vomiting and severe pain. The first patient was transferred to the ICU after 12 h, the others with symptoms four hours later. Lymphocytes and monocytes were rapidly diminishing to zero. Multi-organ failure developed. The diagnosis was “cytokine storm” resulting in angioedema with swelling of skin and mucous membranes. For treatment, corticosteroids were administered, the subjects were taken on ventilators to ease breathing and the plasma was exchanged. Five subjects were released from hospital within one month, one on June 26. Permanent damage could not be excluded.
Following thorough evaluation, the MHRA came to the conclusion that there were no preclinical deficiencies, neither in vitro nor in vivo, that the description of results from the raw data was exact, that there were no undisclosed results, and that the CRO processes and records were OK [17]. However, the tested dose of 0.1 mg/kg leads to 86-91% receptor occupancy and the question was raised whether this might be too high for a first dose in man.
The German health authority, BfArm, checked the manufacture, testing, storage, and distribution facilities at Boehringer Ingelheim and could not find any issues.
The German Paul-Ehrlich Institute recommended to re-evaluate the predictive value of animal experiments and to perform dose calculation for the first dose based on the no-effect level instead of the NOAEL.
An expert group established by the UK health minister and led by Gordon Duff came to the conclusion that the study had not considered what constituted a safe dose in humans, and that current law had not required it [18, 19].
My personal conclusions are that animal models may not be predictive, in particular when
  • The immune system is the target
  • The target is of “essential importance”
  • Human or humanized antibodies are used in animal experiments
  • Receptor binding characteristics of the human or humanized antibody in animals vs. humans are not completely known.
  • In high-risk Phase I experiments, the time difference between drug administrations to subjects must allow for sufficient observation time
The latter point seemed to be generally adopted after the TGN1412 incidence and it should be strictly followed even if earlier experience with a drug seems to indicate that there are no issues to be expected. In the case of BIA 10-2474, it was not strictly followed in the 50-mg group with multiple doses since earlier results seemed to indicate sufficient safety of the drug.
4. FG7142
FG7142 is a small molecule, its chemical structure is provided in Fig. 1. The drug was developed by Schering AG, Berlin, in the early eighties. The compound had been isolated from human urine and is a betacarboline with high affinity for the benzodiazepine receptor, binding at the GABAA receptor site. It was originally considered to be the endogenous benzodiazepine possessing anxiolytic properties.
In preparation of Phase I, many in vitro studies were performed including receptor binding and interaction with other receptors. In vivo, only studies in rodents were performed. Pharmacokinetics indicated a short half-life. In pharmacological and toxicological experiments, mild, non-toxic reactions, mostly slight motor activation and no indications of untoward effects were observed.
A standard Phase I protocol was established and Ethical Committee approval and Informed Consent by the study volunteers were obtained. A total of five healthy male volunteers, age 30-45 years, all of them MDs and other professionals (all members of the project team), was recruited for the study.
Single oral doses with individual up-titration from 50 to 100-200 mg, in one case up to 400 mg were tested. In total, twelve drug administrations were performed. Plasma levels of active drug, cortisol, growth hormone and prolactin were measured and electroencephalograms (EEGs) were monitored. Subjective effects were documented by continuous interviews and sometimes by video recordings.
Three subjects were dosed from 50 to 100-200 mg without any side effects. Plasma levels of FG7142 were undetectable (< 2 ng/ml). Two volunteers, both MDs with considerable experience with CNS-active drugs and Phase I studies, no history of psychic disease, anxiety or panic attacks, administered up to 200 mg and 400 mg, respectively, achieved very high plasma levels of FG7142 (Fig. 2) and of stress hormones (Fig. 3). They experienced dramatic side effects [20].

The time course of events in subject A (200 mg FG7142 orally, no effects after 100 mg) was as follows:

Severe anxiety associated with intense inner strain and excitation starting 50 min after dosing

Unable to speak for several minutes after the onset

Flushes of the face and extremities, accompanied by a feeling of warmth

Blood pressure increase from 105/50 to 160/100 mm Hg

Pulse rate increase from 80 to 110/min

Within 15 min agitation increased, leading to almost intolerable inner tension

The subject walked in circles round the ward, breathing heavily and quickly with sensations of precordial pressure and palpitations

The effects peaked at 1 h and lasted for 2 h, accompanied by verbal aggression and conspicuous alertness

EEGs showed no signs of a convulsive or pre-convulsive state

Subject B was investigated one month later. He received 400 mg FG7142 orally. He had not experienced any side effect up to 200 mg. Plasma levels of active drug after 200 mg were below the detection limit of 2 ng/ml. Ten minutes after 400 mg, effects started to evolve similar to those in subject A after 200 mg. They lasted for 2 min and were accompanied by facial flushes, tremor and cold sweat. After 25 min, a stronger attack started with feelings of severe anxiety, inability to concentrate, and increasing inner tension and excitation. There was an impending fear of death or annihilation. The subject profusely sweated. At the start of a third wave of attacks at 48 min, the subject asked for the injection of an antidote (1mg lormetazepam), which immediately stopped all side effects.
Evaluation of the study results revealed that high plasma levels of FG7142 correlated with strong side effects. The huge differences in bioavailability of FG7142 between subjects could not be explained at that time because the concept of slow and fast metabolizers due to geno- or phenotypic differences in the capability and/or capacity of enzyme systems was unknown. Much later it turned out that subject A is a slow metabolizer. The status of metabolism of subject B is unknown.
Later animal experiments revealed that FG7142 is a partial inverse agonist at the benzodiazepine receptor [21, 22]. An inverse agonist binds to the receptor without stimulating or blocking it but with eliciting the opposite effect of agonists. More preclinical studies, in particular in monkeys, prior to Phase I would potentially have been helpful in identifying and avoiding the later problems early on.
My personal conclusions are
The determination of plasma levels of active drug in Phase I is of essential importance. In the case of FG7142, only pharmacokinetics could (partially) explain the chain of events.
With FG7142, non-linear pharmacokinetics, potentially in combination with a poor metabolizer status of two of the subjects, resulted in a steep increase in bioavailability and therefore in plasma levels of active drug, which provoked the strong side effects observed in the study.
The geno- or phenotypic status of the metabolizing systems of subjects taking part in Phase I rarely is available at that point of time. This knowledge might potentially have prevented the events that happened with FG7142 (and with BIA 10-2474).

Ⅲ. 결론 및 시사점(conclusion)

In summary, animal studies are poor predictors for the outcome of Phase I studies regarding CNS-active drugs and compounds acting on the immune system since humans greatly differ from animals with respect to these two systems. The following actions are therefore strongly recommended
  •  Never test several volunteers at the same time or with too short intervals between administrations
  •  When studying monoclonal antibodies, extrapolation from animal results to humans is particularly challenging due to
    • Immunogenicity reactions in animals towards human or humanized antibodies, which can make studies impossible altogether in some species
    • Hypersensitivity in humans
    • Different availability or distribution of receptors
    • Different characteristics of the animal and human immune systems
  • When studying drugs acting on the CNS, be careful in the extrapolation from animals to humans, in particular in the assumption “the drug is safe”, since many effects observed later in humans might not be detected easily in animals.
  • Up-titrate every subject individually due to potential differences in metabolism or individual sensitivity.
  • Do not extrapolate from one subject to the next in case of positive outcomes (“good tolerability of the drug”). Only make analogy conclusions if the outcomes were negative.
  • Always measure plasma levels in Phase I in parallel to other testing
  • As an additional measure, the determination of the metabolizer status of each subject (slow or fast metabolizer) would be helpful.
  • The latter of course requires profound knowledge of the metabolism of the drug, both in vitro (in animal and in human enzyme systems) and in vivo in animals.
  • Some general recommendations include:
    • Do not give in to pressure from Management or others for “fast development”.
    • The more you know about a drug, the safer is Phase I.
  • Taking the above into account, Phase I studies should be the safest part of clinical drug development.
테이블이미지
Table 1. FAAH inhibitors and their status of development
이미지1
Figure 1. Chemical structures of BIA 10-2474 (left) and of FG7142 (right).
이미지2
Figure 2. Plasma levels of FG7142 in two subjects, dosed 200 mg and 400 mg, respectively
이미지3
Figure 2. Plasma levels of FG7142 in two subjects, dosed 200 mg and 400 mg, respectively

참고문헌 및 출처(Reference)

  1. L. E. Kiss, D. A. Learmonth, C. P. Da Costa Pereira Rosa, R. Gusmão De Noronha, P. N. L. Palma, P. M. V. A. Soares Da Silva, A. Beliaev, Pharmaceutical Compounds, WO 2010074588 (2010).
  2. L. E. Kiss, R. Gusmão De Noronha, C. P. Da Costa Pereira Rosa, R. Pinto, Urea compounds and their use as FAAH enzyme inhibitors, WO 2015016729 (2015).
  3. www.biotrial.com
  4. Essai thérapeutique mortel à Biotrial Rennes. Le contenu du test du Bia 10 – 2474 de Bial révélé, Breizh-info.com. January 15, 2016.
  5. Essai clinique BIA-102474-101 du laboratoire BIAL: Publication du protocole clinique, Agence Nationale de Sécurité du Médicament et des Produits de Santé. January 22, 2016.
  6. La survenue d’effets graves ayant entraîné l’hospitalisation de 6 patients, dont un en état de mort cérébrale, a conduit à l’arrêt premature d’un essai clinique du laboratoire BIAL - Point d'information". Agence Nationale de Sécurité du Médicament, France (ANSM). January 15, 2016.
  7. Accident grave dans le cadre d’un essai clinique - Intervention de Marisol Touraine à Rennes, Ministère des Affaires Sociales, de la Santé et des Droits des Femmes, January 15, 2016.
  8. M. Enserink, What we know so far about clinical trial disaster in France, Science Editorial (January 15th, 2016).
  9. D. Butler, E. Callaway, Scientists in the dark after French clinical trial proves fatal, Nature 529: 263-4 (2016).
  10. M. Eddleston, A. F. Cohen, D. J. Webb. "Editorial - Implications of the BIA-102474-101 study for review of first-into-human clinical trials" Br J Clin Pharmacol 81: 582–586 (2016).
  11. Note D’etape: Enquete sur des Incidents Graves Survenus dans le Cadre de la Realisation d’un Essai Clinique, Inspection générale des affaires sociales. February 5, 2016.
  12. Intervention de Marisol Touraine, Conférence de presse, Accident d’essai clinique, point d’étape, Ministère des Affaires Sociales, de la Santé et des Droits des Femmes, February 4, 2016.
  13. Janssen Research & Development, LLC, Press Release, January 17, 2016.
  14. Minutes of the Temporary Specialist Scientific Committee (TSSC) meeting on "FAAH (Fatty Acid Amide Hydrolase) Inhibitors" of 15/02/2016 (08/03/2016)". Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM). March 7, 2016.
  15. C.-H. Lin, T. Kerkau, C. Guntermann, M. Trischler, N.Beyersdorf, Y. Scheuring, H.-P. Tony, C. Kneitz, M. W., P.Mueller, T. Huenig, T. Hanke, Superagonistic Anti-CD28 Antibody TGN1412 as a Potential Immunotherapeutic for the Treatment of B Cell Chronic Lymphocytic Leukemia, Blood 104 (11): Abstract 2519 (2004).
  16. TGN1412 Investigator Brochure, www.gov.uk/mhra.
  17. Investigations into adverse incidents during clinical trials of TGN1412, www.gov.uk/mhra.
  18. Expert Group on Phase One Clinical Trials (chairman: Professor Gordon W. Duff). Expert group on phase one clinical trials: Final report. TSO (The Stationary Office). (2006).
  19. C. J. Horvath, M. N. Milton, The TeGenero Incident and the Duff Report Conclusions: A Series of Unfortunate Events or an Avoidable Event? Toxicologic Pathology 37: 372-383 (2009).
  20. R. Dorow, R. Horowski, G. Paschelke, M. Amin, Severe Anxiety Induced by FG7142, a -carboline Ligand for Benzodiazepine Receptors, Lancet 2(8341): 98-9 (1983).
  21. L. H. Jensen, E. N. Petersen, C. Braestrup, Audigenic Seizures in DBA/2 Mice Discriminate Sensitively between low Efficacy Benzodiazepine Receptor Agonists and Inverse Agonists. Life Sci. 33(4):393-9 (1983).
  22. P. Pole, E. P. Bonetti, R. Schaffner, W. Haefely, A three-state model of the benzodiazepine receptor explains the interactions between the benzodiazepine antagonist Ro15-1788, benzodiazepine tranquilizers, -carbolines, and phenobarbitone. Naunyn-Schmiedeberg’s Arch Pharmacol 321: 260-64 (1982).

약력(Profile)

Since 09/15: VivoTecc GmbH, Berlin, Germany, CEO, co-founder
Since 10/14: Independent consultant
2009-09/2014: Bayer Healthcare, Berlin; Global Project Management; globally responsible for the evaluation of external license offers and M&A possibilities in all therapeutic areas of Bayer Pharma and all stages of R&D.
1999-2009: Schering AG, Berlin (1999-2002), Berlex (affiliate of Schering AG; 2002-2006), Montville, NJ, USA and Bayer Schering Pharma (2006-2009), Montville, NJ, USA; Global Program Management; globally responsible Project Leader in the therapeutic areas neurology, gastroenterology and oncology
1998: Portfolio Management Diagnostics, Schering AG, Berlin; head; responsible for portfolio planning in the Global Business Unit Diagnostics and Radiopharmaceuticals
1990-1998: Schering AG, Berlin; X-Ray Contrast Media Research; head of a department with responsibility for the chemical synthesis, physicochemical and preclinical characterization of X-ray contrast agents and in-vitro and in-vivo imaging in Berlin; coordination of research at the joint venture company, CIJISA SA, Madrid, Spain, and with several cooperation partners, such as Biophysica, San Diego, CA, USA
1985-1990: Schering AG, Berlin; Research Team Central Nervous System (CNS); head; responsible for all aspects of R&D in the CNS field at Schering AG / leading a team of scientists ranging from basic research to clinical development
1977-1985: Schering AG, Berlin, Pharmacokinetics and Drug Metabolism; scientist (1977-1984), department head (1985-1990); responsible for all aspects of pharmacokinetics and drug metabolism in-vitro, in animals and in humans
Education:
Ph.D. in Chemistry, University of Erlangen, Germany (1976)
Professor for Pharmacology & Toxicology, Medical School, Free University, Berlin, Germany (1995)
Professor for Pharmacology & Toxicology, Medical School, Charité, Berlin, Germany (1996 – present)
Professional Affiliations:
German Chemical Society (GdCh), Sections Analytical Chemistry and Medicinal Chemistry
German Society for Pharmacology and Toxicology
German Roentgenological Society (1990-2000)
Member of the European COST Chemistry D13 (New Molecules Towards Human Health Care) Management Committee (1998 – 2003)
Evaluator for the Sixth (FP6) and Seventh (FP7) European Framework Program for Research and Technological Development (2003 – present)
Mentor of several Ph.D. students (1995 – present)
Publications: Approx. 200
Patent Applications: Approx. 90
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