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Digital Therapeutics: A Threat or Opportunity to Pharmaceuticals


Digital Therapeutics: A Threat or Opportunity to Pharmaceuticals

Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Digital Therapeutics (DTx) have been defined by the Digital Therapeutics Alliance (DTA) as “delivering evidence based therapeutic interventions to patients, that are driven by software to prevent, manage or treat a medical disorder or disease”. They might come in the form of a smart phone or computer tablet app, or some form of a cloud-based service connected to a wearable device. DTx tend to fall into three groups. Firstly, developers and mental health researchers have built digital solutions which typically provide a form of software delivered Cognitive-Behaviour Therapies (CBT) that help patients change behaviours and develop coping strategies around their condition. Secondly there are the group of Digital Therapeutics which target lifestyle issues, such as diet, exercise and stress, that are associated with chronic conditions, and work by offering personalized support for goal setting and target achievement. Lastly, DTx can be designed to work in combination with existing medication or treatments, helping patients manage their therapies and focus on ensuring the therapy delivers the best outcomes possible.

 

Pharmaceutical companies are clearly trying to understand what DTx will mean for them. They want to analyze whether it will be a threat or opportunity to their business. For a long time, they have been providing additional support services to patients who take relatively expensive drugs for chronic conditions. A nurse-led service might provide visits and telephone support to diabetics for example who self-inject insulin therapies. But DTx will help broaden the scope of support services because they can be delivered cost-effectively, and importantly have the ability to capture real-world evidence on patient outcomes. They will no-longer be reserved for the most expensive drugs or therapies but could apply to a whole range of common treatments to boost their efficacy. Faced with the arrival of Digital Therapeutics either replacing drugs, or playing an important role alongside therapies, pharmaceutical firms have three options. They can either ignore DTx and focus on developing drug therapies as they have done; they can partner with a growing number of DTx companies to develop software and services complimenting their drugs; or they can start to build their own Digital Therapeutics to work with their products.

 

Digital Therapeutics will have knock-on effects in health industries, which may be as great as the introduction of therapeutic apps and services themselves. Together with connected health monitoring devices, DTx will offer a near constant stream of data about an individuals’ behavior, real world context around factors affecting their treatment in their everyday lives and emotional and physiological data such as blood pressure and blood sugar levels. Analysis of the resulting data will help create support services tailored to each patient. But who stores and analyses this data is an important question. Strong data governance will be paramount to maintaining trust, and the highly regulated pharmaceutical industry may not be best-placed to handle individual patient data. Meanwhile, the health sector (payers and healthcare providers) is becoming more focused on patient outcomes, and payment for value not volume. The future will say whether pharmaceutical firms enhance the effectiveness of drugs with DTx, or in some cases replace drugs with DTx.

 

Digital Therapeutics have the potential to change what the pharmaceutical industry sells: rather than a drug it will sell a package of drugs and digital services. But they will also alter who the industry sells to. Pharmaceutical firms have traditionally marketed drugs to doctors, pharmacists and other health professionals, based on the efficacy of a specific product. Soon it could be paid on the outcome of a bundle of digital therapies, medicines and services with a closer connection to both providers and patients. Apart from a notable few, most pharmaceutical firms have taken a cautious approach towards Digital Therapeutics. Now, it is to be observed that how the pharmaceutical companies use DTx to their benefit as well as for the benefit of the general population.

 

References:

 

https://eloqua.eyeforpharma.com/LP=23674?utm_campaign=EFP%2007MAR19%20EFP%20Database&utm_medium=email&utm_source=Eloqua&elqTrackId=73e21ae550de49ccabbf65fce72faea0&elq=818d76a54d894491b031fa8d1cc8d05c&elqaid=43259&elqat=1&elqCampaignId=24564

 

https://www.s3connectedhealth.com/resources/white-papers/digital-therapeutics-pharmas-threat-or-opportunity/

 

http://www.pharmatimes.com/web_exclusives/digital_therapeutics_will_transform_pharma_and_healthcare_industries_in_2019._heres_how._1273671

 

https://www.mckinsey.com/industries/pharmaceuticals-and-medical-products/our-insights/exploring-the-potential-of-digital-therapeutics

 

https://player.fm/series/digital-health-today-2404448/s9-081-scaling-digital-therapeutics-the-opportunities-and-challenges

 

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Parasites and Cancer

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

FEATURED ONLINE HIGHLIGHT
Featured Online Highlight
NEJM QUICK TAKE

Can malignant transformation of parasite cells cause neoplasms in an immunosuppressed host? New research findings are summarized in a short video.

Teaching Topic
Nivolumab in Renal-Cell Carcinoma
ORIGINAL ARTICLE

R.J. Motzer and Others

Free Full Text   CME Exam  Comments

Each year, an estimated 338,000 new cases of renal-cell carcinoma are diagnosed worldwide, and approximately 30% of patients present with metastatic disease at the time of diagnosis. A number of targeted therapies have been approved for the treatment of advanced or metastatic renal-cell carcinoma. Although everolimus and other agents have changed the therapeutic landscape for this disease, these treatments are associated with limited overall survival after a given agent is no longer effective. Motzer et al. conducted a randomized, open-label, phase 3 study that compared nivolumab with everolimus in patients with advanced renal-cell carcinoma, who had previously received one or two cycles of antiangiogenic therapy.

Clinical Pearls
Clinical Pearl  Does nivolumab as compared to everolimus prolong survival in patients with renal-cell carcinoma who have previously received one or two cycles of antiangiogenic therapy?

In the study by Motzer et al., patients with advanced renal-cell carcinoma who had received previous antiangiogenic treatment had longer survival with nivolumab treatment than with everolimus treatment. The median overall survival was 25.0 months (95% confidence interval [CI], 21.8 to not estimable) in the nivolumab group and 19.6 months (95% CI, 17.6 to 23.1) in the everolimus group. Death occurred in 183 of the 410 patients (45%) randomly assigned to receive nivolumab and in 215 of the 411 patients (52%) randomly assigned to receive everolimus. The hazard ratio for death (from any cause) with nivolumab versus everolimus was 0.73 (98.5% CI, 0.57 to 0.93; P=0.002), which met the prespecified criterion for superiority.

Figure 1. Kaplan–Meier Curve for Overall Survival.

Clinical Pearl  Is nivolumab associated with a higher objective response rate than everolimus in previously treated patients?

In the study by Motzer et al., the objective response rate was higher with nivolumab than with everolimus (25% vs. 5%; odds ratio 5.98; 95% CI, 3.68 to 9.72; P<0.001). Partial responses were observed in 99 patients (24%) in the nivolumab group and in 20 patients (5%) in the everolimus group. Complete responses were observed in 4 patients (1%) in the nivolumab group and in 2 patients (<1%) in the everolimus group.

Morning Report Questions
Q. Is nivolumab associated with fewer treatment-related adverse events as compared to everolimus?

A. In the Motzer trial, treatment-related adverse events of any grade occurred in 319 of the 406 patients (79%) treated with nivolumab and in 349 of the 397 patients (88%) treated with everolimus. Grade 3 or 4 treatment-related adverse events occurred in 76 of the 406 patients (19%) treated with nivolumab and in 145 of the 397 patients (37%) treated with everolimus; the most common grade 3 or grade 4 event was fatigue (10 patients, 2%) with nivolumab and anemia (31 patients, 8%) with everolimus.

Table 2. Treatment-Related Adverse Events Reported in 10% or More of Treated Patients in Either Group.

Q. Was the benefit observed with nivolumab in the Motzer study linked to programmed death 1 ligand (PD-L1) expression in tumors?

A. A benefit was observed with nivolumab irrespective of PD-L1 expression. Nivolumab has been reported to be associated with pharmacodynamic changes in blood and tumor markers that are consistent with PD-1 inhibition. The study data corroborate previous studies that have indicated that higher levels of PD-L1 expression are associated with poorer survival in renal-cell carcinoma, but they do not support PD-L1 as a marker of treatment benefit in renal-cell carcinoma. The relationship between PD-L1 expression and outcomes after treatment with nivolumab appears to depend on tumor type and histologic class. An association between PD-L1 expression and improved outcomes with nivolumab treatment has been observed for metastatic melanoma and only some types of lung cancer.

Figure 3. Kaplan–Meier Curve for Overall Survival, According to Programmed Death 1 Ligand (PD-L1) Expression Level.

 

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Victoria Hale: Pharmaceutical Pioneer

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Bringing Life-Saving Medicine to Those Who Can Least Afford It

http://www.genengnews.com/insight-and-intelligence/victoria-hale-pharmaceutical-pioneer/77900545/

The quest for innovative, affordable, and sustainable medical solutions for women has driven Victoria Hale, Ph.D., to start multiple companies. [iStock/© zodebala]

http://www.genengnews.com/media/images/AnalysisAndInsight/Oct27_2015_iStock_22080713_FamilyPoverty1381802542.jpg

http://www.genengnews.com/Media/images/AnalysisAndInsight/oct27_2015_VictoriaHale_Headshot5521815813.jpg

  • Three years into working for Genentech, Victoria Hale, Ph.D., faced a pivotal moment. Her career was on track to becoming a high-ranking, well-paid executive in one of the major pharmaceutical companies. Instead, she quit her job to create a whole new model for the way pharmaceuticals are developed.

Prior to Genentech, while working at the FDA, she witnessed an example of what happens to medicines for unprofitable markets. A pharmaceutical company was developing one new drug for two promising indications, one a potential blockbuster and the other an orphan disease. Corporate executives decided to focus on the blockbuster and abandon the orphan disease because it distracted the team from the more profitable indication.

Dr. Hale saw this as a glaring injustice.

“I felt that it was important to make drugs for everyone who needs them, regardless of whatever level they can pay,” she says. “People cannot develop medicines themselves. Experienced, trained professionals are the only ones who know how to do this. There are people who have medicines for any disease here, while 5,000 miles away babies are dying for lack of simple medications.”

Observing the inequities in how drugs were distributed, she asked a fundamental question: “What if we removed the profit requirement? What if we created a nonprofit model for developing pharmaceuticals?”

As someone with a Ph.D. in pharmaceutical chemistry from the University of California San Francisco, Dr. Hale was well aware that bringing a new drug to market can cost in the billions. Her strategy, with a future nonprofit, was to find drugs with patents that had expired or which were not being used because of low profit margins. Even so, getting governmental approval for a new use for an existing drug can cost $50 million.

  • Struck a Chord

Nevertheless her vision of creating a nonprofit model for addressing injustices in how drugs are distributed began attracting donors. Her first major fundraising success came when the Gates Foundation provided her with a $4.7 million check for seed money. In the years since, she has been granted $150 million in total for several programs. Other philanthropic organizations have continued to fund her efforts, and, surprisingly, if not amazingly, Dr. Hale was able to find an anonymous donor who provided an $82 million grant to fund low-cost highly effective contraception efforts.

Dr. Hale can point to many examples of how this nonprofit approach has successfully played out in practice. One example is the work that the company she founded in 2000, OneWorld Health, is doing in providing a cure for black fever. This is a disease that has historically infected a million people a year in India leading to 300,000 death annually.

Black fever, or visceral leishmaniasis, is a disease of the poor. A malnourished person may have a compromised immune system, making him or her vulnerable to the parasite that causes leishmaniasis.

“When I was first looking into black fever,” remembers Dr. Hale, “there was a treatment available, but the cost was more than $100, and families faced the choice of going into debt for three generations or allowing the family member to die.”

Dr. Hale learned of an injectable antibiotic, paromomycin, that was apparently effective against the parasite in the laboratory setting. It hadn’t been formally studied in people for use against black fever, and there was no money to continue further research on it, so although a cure existed, it hadn’t been proven and it wasn’t available for those who needed it. However, using her nonprofit approach, Dr. Hale and her colleagues were able to raise the $50 million from the Gates Foundation for clinical trials in India, and succeeded in demonstrating efficacy and safety.

Today, Dr. Hale, who was awarded the 2015 Award for Leadership in Women’s Health Worldwide at the 23rd Annual Congress of the Academy of Women’s Health, and her colleagues are able to produce paromomycin for $10 per treatment. As a result, and combined with other public health interventions, India may soon be free of this scourge.

Another of Dr. Hale’s concerns is unwanted pregnancy. Her organization Medicines360 is able to provide an IUD that has a 40-fold greater success rate than the pill, it lasts for three years, and is sold for $50 each to women who lack adequate insurance. Medicines360 makes it available to family planning clinics that provide services to low-income women. The consequences for women and for society are incalculable.

Like OneWorld Health, Medicines360 is also a new approach to pharmaceuticals. Medicines360 is particularly aimed at pharmaceuticals for women, and it has a unique operating model: it reinvests profits generated through commercial sales revenue and puts these profits into advocacy, education, research, and development. The goal is to provide innovative, affordable, and sustainable medical solutions for women.

For Medicines360, profits aren’t the motive; they’re the means to a mission. Dr. Hale believes that her nonprofit can be a model for other nonprofit pharmaceutical companies and also for hybrid companies that could get part of their funding from philanthropists and part from traditional sources. She already knows that there are young idealistic people who will carry the model forward and who are pushing this agenda.

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Treatment of Acute Leukemias

Author and Curator: Larry H. Bernstein, MD, FCAP

2.4.4 Treatment of Acute Leukemias

Treatment of Acute Lymphoblastic Leukemia

Ching-Hon Pu, and William E. Evans
N Engl J Med Jan 12, 2006; 354:166-178
http://dx.doi.org:/10.1056/NEJMra052603

Although the overall cure rate of acute lymphoblastic leukemia (ALL) in children is about 80 percent, affected adults fare less well. This review considers recent advances in the treatment of ALL, emphasizing issues that need to be addressed if treatment outcome is to improve further.

Acute Lymphoblastic Leukemia

Ching-Hon Pui, Mary V. Relling, and James R. Downing
N Engl J Med Apr 8, 2004; 350:1535-1548
http://dx.doi.org:/10.1056/NEJMra023001

This comprehensive survey emphasizes how recent advances in the knowledge of molecular mechanisms involved in acute lymphoblastic leukemia have influenced diagnosis, prognosis, and treatment.

Gene-Expression Patterns in Drug-Resistant Acute Lymphoblastic Leukemia Cells and Response to Treatment

Amy Holleman, Meyling H. Cheok, Monique L. den Boer, et al.
N Engl J Med 2004; 351:533-42

Childhood acute lymphoblastic leukemia (ALL) is curable with chemotherapy in approximately 80 percent of patients. However, the cause of treatment failure in the remaining 20 percent of patients is largely unknown.

Methods We tested leukemia cells from 173 children for sensitivity in vitro to prednisolone, vincristine, asparaginase, and daunorubicin. The cells were then subjected to an assessment of gene expression with the use of 14,500 probe sets to identify differentially expressed genes in drug-sensitive and drug-resistant ALL. Gene-expression patterns that differed according to sensitivity or resistance to the four drugs were compared with treatment outcome in the original 173 patients and an independent cohort of 98 children treated with the same drugs at another institution.

Results We identified sets of differentially expressed genes in B-lineage ALL that were sensitive or resistant to prednisolone (33 genes), vincristine (40 genes), asparaginase (35 genes), or daunorubicin (20 genes). A combined gene-expression score of resistance to the four drugs, as compared with sensitivity to the four, was significantly and independently related to treatment outcome in a multivariate analysis (hazard ratio for relapse, 3.0; P=0.027). Results were confirmed in an independent population of patients treated with the same medications (hazard ratio for relapse, 11.85; P=0.019). Of the 124 genes identified, 121 have not previously been associated with resistance to the four drugs we tested.

Conclusions  Differential expression of a relatively small number of genes is associated with drug resistance and treatment outcome in childhood ALL.

Leukemias Treatment & Management

Author: Lihteh Wu, MD; Chief Editor: Hampton Roy Sr
http://emedicine.medscape.com/article/1201870-treatment

The treatment of leukemia is in constant flux, evolving and changing rapidly over the past few years. Most treatment protocols use systemic chemotherapy with or without radiotherapy. The basic strategy is to eliminate all detectable disease by using cytotoxic agents. To attain this goal, 3 phases are typically used, as follows: remission induction phase, consolidation phase, and maintenance therapy phase.

Chemotherapeutic agents are chosen that interfere with cell division. Tumor cells usually divide more rapidly than host cells, making them more vulnerable to the effects of chemotherapy. Primary treatment will be under the direction of a medical oncologist, radiation oncologist, and primary care physician. Although a general treatment plan will be outlined, the ophthalmologist does not prescribe or manage such treatment.

  • The initial treatment of ALL uses various combinations of vincristine, prednisone, and L-asparaginase until a complete remission is obtained.
  • Maintenance therapy with mercaptopurine is continued for 2-3 years following remission.
  • Use of intrathecal methotrexate with or without cranial irradiation to cover the CNS varies from facility to facility.
  • Daunorubicin, cytarabine, and thioguanine currently are used to obtain induction and remission of AML.
  • Maintenance therapy for 8 months may lengthen remission. Once relapse has occurred, AML generally is curable only by bone marrow transplantation.
  • Presently, treatment of CLL is palliative.
  • CML is characterized by a leukocytosis greater than 100,000 cells. Emergent treatment with leukopheresis sometimes is necessary when leukostastic complications are present. Otherwise, busulfan or hydroxyurea may control WBC counts. During the chronic phase, treatment is palliative.
  • When CML converts to the blastic phase, approximately one third of cases behave as ALL and respond to treatment with vincristine and prednisone. The remaining two thirds resemble AML but respond poorly to AML therapy.
  • Allogeneic bone marrow transplant is the only curative therapy for CML. However, it carries a high early mortality rate.
  • Leukemic retinopathy usually is not treated directly. As the hematological parameters normalize with systemic treatment, many of the ophthalmic signs resolve. There are reports that leukopheresis for hyperviscosity also may alleviate intraocular manifestations.
  • When definite intraocular leukemic infiltrates fail to respond to systemic chemotherapy, direct radiation therapy is recommended.
  • Relapse, manifested by anterior segment involvement, should be treated by radiation. In certain cases, subconjunctival chemotherapeutic agents have been injected.
  • Optic nerve head infiltration in patients with ALL is an emergency and requires prompt radiation therapy to try to salvage some vision.

Treatments and drugs

http://www.mayoclinic.org/diseases-conditions/leukemia/basics/
treatment/con-20024914

Common treatments used to fight leukemia include:

  • Chemotherapy. Chemotherapy is the major form of treatment for leukemia. This drug treatment uses chemicals to kill leukemia cells.

Depending on the type of leukemia you have, you may receive a single drug or a combination of drugs. These drugs may come in a pill form, or they may be injected directly into a vein.

  • Biological therapy. Biological therapy works by using treatments that help your immune system recognize and attack leukemia cells.
  • Targeted therapy. Targeted therapy uses drugs that attack specific vulnerabilities within your cancer cells.

For example, the drug imatinib (Gleevec) stops the action of a protein within the leukemia cells of people with chronic myelogenous leukemia. This can help control the disease.

  • Radiation therapy. Radiation therapy uses X-rays or other high-energy beams to damage leukemia cells and stop their growth. During radiation therapy, you lie on a table while a large machine moves around you, directing the radiation to precise points on your body.

You may receive radiation in one specific area of your body where there is a collection of leukemia cells, or you may receive radiation over your whole body. Radiation therapy may be used to prepare for a stem cell transplant.

  • Stem cell transplant. A stem cell transplant is a procedure to replace your diseased bone marrow with healthy bone marrow.

Before a stem cell transplant, you receive high doses of chemotherapy or radiation therapy to destroy your diseased bone marrow. Then you receive an infusion of blood-forming stem cells that help to rebuild your bone marrow.

You may receive stem cells from a donor, or in some cases you may be able to use your own stem cells. A stem cell transplant is very similar to a bone marrow transplant.

2.4.4.2 Acute Myeloid Leukemia

New treatment approaches in acute myeloid leukemia: review of recent clinical studies.

Norsworthy K1Luznik LGojo I.
Rev Recent Clin Trials. 2012 Aug; 7(3):224-37.
http://www.ncbi.nlm.nih.gov/pubmed/22540908

Standard chemotherapy can cure only a fraction (30-40%) of younger and very few older patients with acute myeloid leukemia (AML). While conventional allografting can extend the cure rates, its application remains limited mostly to younger patients and those in remission. Limited efficacy of current therapies and improved understanding of the disease biology provided a spur for clinical trials examining novel agents and therapeutic strategies in AML. Clinical studies with novel chemotherapeutics, antibodies, different signal transduction inhibitors, and epigenetic modulators demonstrated their clinical activity; however, it remains unclear how to successfully integrate novel agents either alone or in combination with chemotherapy into the overall therapeutic schema for AML. Further studies are needed to examine their role in relation to standard chemotherapy and their applicability to select patient populations based on recognition of unique disease and patient characteristics, including the development of predictive biomarkers of response. With increasing use of nonmyeloablative or reduced intensity conditioning and alternative graft sources such as haploidentical donors and cord blood transplants, the benefits of allografting may extend to a broader patient population, including older AML patients and those lacking a HLA-matched donor. We will review here recent clinical studies that examined novel pharmacologic and immunologic approaches to AML therapy.

Novel approaches to the treatment of acute myeloid leukemia.

Roboz GJ1
Hematology Am Soc Hematol Educ Program. 2011:43-50.
http://dx.doi.org:/10.1182/asheducation-2011.1.43.

Approximately 12 000 adults are diagnosed with acute myeloid leukemia (AML) in the United States annually, the majority of whom die from their disease. The mainstay of initial treatment, cytosine arabinoside (ara-C) combined with an anthracycline, was developed nearly 40 years ago and remains the worldwide standard of care. Advances in genomics technologies have identified AML as a genetically heterogeneous disease, and many patients can now be categorized into clinicopathologic subgroups on the basis of their underlying molecular genetic defects. It is hoped that enhanced specificity of diagnostic classification will result in more effective application of targeted agents and the ability to create individualized treatment strategies. This review describes the current treatment standards for induction, consolidation, and stem cell transplantation; special considerations in the management of older AML patients; novel agents; emerging data on the detection and management of minimal residual disease (MRD); and strategies to improve the design and implementation of AML clinical trials.

Age ≥ 60 years has consistently been identified as an independent adverse prognostic factor in AML, and there are very few long-term survivors in this age group.5 Poor outcomes in elderly AML patients have been attributed to both host- and disease-related factors, including medical comorbidities, physical frailty, increased incidence of antecedent myelodysplastic syndrome and myeloproliferative disorders, and higher frequency of adverse cytogenetics.28 Older patients with multiple poor-risk factors have a high probability of early death and little chance of long-term disease-free survival with standard chemotherapy. In a retrospective analysis of 998 older patients treated with intensive induction at the M.D. Anderson Cancer Center, multivariate analysis identified age ≥ 75 years, unfavorable karyotype, poor performance status, creatinine > 1.3 mg/dL, duration of antecedent hematologic disorder > 6 months, and treatment outside a laminar airflow room as adverse prognostic indicators.29 Patients with 3 or more of these factors had expected complete remission rates of < 20%, 8-week mortality > 50%, and 1-year survival < 10%. The Medical Research Council (MRC) identified cytogenetics, WBC count at diagnosis, age, and de novo versus secondary disease as critical factors influencing survival in > 2000 older patients with AML, but cautioned in their conclusions that less objective factors, such as clinical assessment of “fitness” for chemotherapy, may be equally important in making treatment decisions in this patient population.30 It is hoped that data from comprehensive geriatric assessments of functional status, cognition, mood, quality of life, and other measures obtained during ongoing cooperative group trials will improve our ability to predict how older patients will tolerate treatment.

Current treatment of acute myeloid leukemia.

Roboz GJ1.
Curr Opin Oncol. 2012 Nov; 24(6):711-9.
http://dx.doi.org:/10.1097/CCO.0b013e328358f62d.

The objectives of this review are to discuss standard and investigational nontransplant treatment strategies for acute myeloid leukemia (AML), excluding acute promyelocytic leukemia.

RECENT FINDINGS: Most adults with AML die from their disease. The standard treatment paradigm for AML is remission induction chemotherapy with an anthracycline/cytarabine combination, followed by either consolidation chemotherapy or allogeneic stem cell transplantation, depending on the patient’s ability to tolerate intensive treatment and the likelihood of cure with chemotherapy alone. Although this approach has changed little in the last three decades, increased understanding of the pathogenesis of AML and improvements in molecular genomic technologies are leading to novel drug targets and the development of personalized, risk-adapted treatment strategies. Recent findings related to prognostically relevant and potentially ‘druggable’ molecular targets are reviewed.

SUMMARY: At the present time, AML remains a devastating and mostly incurable disease, but the combination of optimized chemotherapeutics and molecularly targeted agents holds significant promise for the future.

Adult Acute Myeloid Leukemia Treatment (PDQ®)
http://www.cancer.gov/cancertopics/pdq/treatment/adultAML/healthprofessional/page9

About This PDQ Summary

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Treatment Option Overview for AML

Successful treatment of acute myeloid leukemia (AML) requires the control of bone marrow and systemic disease and specific treatment of central nervous system (CNS) disease, if present. The cornerstone of this strategy includes systemically administered combination chemotherapy. Because only 5% of patients with AML develop CNS disease, prophylactic treatment is not indicated.[13]

Treatment is divided into two phases: remission induction (to attain remission) and postremission (to maintain remission). Maintenance therapy for AML was previously administered for several years but is not included in most current treatment clinical trials in the United States, other than for acute promyelocytic leukemia. (Refer to the Adult Acute Myeloid Leukemia in Remission section of this summary for more information.) Other studies have used more intensive postremission therapy administered for a shorter duration of time after which treatment is discontinued.[4] Postremission therapy appears to be effective when given immediately after remission is achieved.[4]

Since myelosuppression is an anticipated consequence of both the leukemia and its treatment with chemotherapy, patients must be closely monitored during therapy. Facilities must be available for hematologic support with multiple blood fractions including platelet transfusions and for the treatment of related infectious complications.[5] Randomized trials have shown similar outcomes for patients who received prophylactic platelet transfusions at a level of 10,000/mm3 rather than 20,000/mm3.[6] The incidence of platelet alloimmunization was similar among groups randomly assigned to receive pooled platelet concentrates from random donors; filtered, pooled platelet concentrates from random donors; ultraviolet B-irradiated, pooled platelet concentrates from random donors; or filtered platelets obtained by apheresis from single random donors.[7] Colony-stimulating factors, for example, granulocyte colony–stimulating factor (G-CSF) and granulocyte-macrophage colony–stimulating factor (GM-CSF), have been studied in an effort to shorten the period of granulocytopenia associated with leukemia treatment.[8] If used, these agents are administered after completion of induction therapy. GM-CSF was shown to improve survival in a randomized trial of AML in patients aged 55 to 70 years (median survival was 10.6 months vs. 4.8 months). In this Eastern Cooperative Oncology Group (ECOG) (EST-1490) trial, patients were randomly assigned to receive GM-CSF or placebo following demonstration of leukemic clearance of the bone marrow;[9] however, GM-CSF did not show benefit in a separate similar randomized trial in patients older than 60 years.[10] In the latter study, clearance of the marrow was not required before initiating cytokine therapy. In a Southwest Oncology Group (NCT00023777) randomized trial of G-CSF given following induction therapy to patients older than 65 years, complete response was higher in patients who received G-CSF because of a decreased incidence of primary leukemic resistance. Growth factor administration did not impact on mortality or on survival.[11,12] Because the majority of randomized clinical trials have not shown an impact of growth factors on survival, their use is not routinely recommended in the remission induction setting.

The administration of GM-CSF or other myeloid growth factors before and during induction therapy, to augment the effects of cytotoxic therapy through the recruitment of leukemic blasts into cell cycle (growth factor priming), has been an area of active clinical research. Evidence from randomized studies of GM-CSF priming have come to opposite conclusions. A randomized study of GM-CSF priming during conventional induction and postremission therapy showed no difference in outcomes between patients who received GM-CSF and those who did not receive growth factor priming.[13,14][Level of evidence: 1iiA] In contrast, a similar randomized placebo-controlled study of GM-CSF priming in patients with AML aged 55 to 75 years showed improved disease-free survival (DFS) in the group receiving GM-CSF (median DFS for patients who achieved complete remission was 23 months vs. 11 months; 2-year DFS was 48% vs. 21%), with a trend towards improvement in overall survival (2-year survival was 39% vs. 27%, = .082) for patients aged 55 to 64 years.[15][Level of evidence: 1iiDii]

References

  1. Kebriaei P, Champlin R, deLima M, et al.: Management of acute leukemias. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2011, pp 1928-54.
  2. Wiernik PH: Diagnosis and treatment of acute nonlymphocytic leukemia. In: Wiernik PH, Canellos GP, Dutcher JP, et al., eds.: Neoplastic Diseases of the Blood. 3rd ed. New York, NY: Churchill Livingstone, 1996, pp 283-302.
  3. Morrison FS, Kopecky KJ, Head DR, et al.: Late intensification with POMP chemotherapy prolongs survival in acute myelogenous leukemia–results of a Southwest Oncology Group study of rubidazone versus adriamycin for remission induction, prophylactic intrathecal therapy, late intensification, and levamisole maintenance. Leukemia 6 (7): 708-14, 1992. [PUBMED Abstract]
  4. Cassileth PA, Lynch E, Hines JD, et al.: Varying intensity of postremission therapy in acute myeloid leukemia. Blood 79 (8): 1924-30, 1992. [PUBMED Abstract]
  5. Supportive Care. In: Wiernik PH, Canellos GP, Dutcher JP, et al., eds.: Neoplastic Diseases of the Blood. 3rd ed. New York, NY: Churchill Livingstone, 1996, pp 779-967.
  6. Rebulla P, Finazzi G, Marangoni F, et al.: The threshold for prophylactic platelet transfusions in adults with acute myeloid leukemia. Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto. N Engl J Med 337 (26): 1870-5, 1997. [PUBMED Abstract]
  7. Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. The Trial to Reduce Alloimmunization to Platelets Study Group. N Engl J Med 337 (26): 1861-9, 1997. [PUBMED Abstract]
  8. Geller RB: Use of cytokines in the treatment of acute myelocytic leukemia: a critical review. J Clin Oncol 14 (4): 1371-82, 1996. [PUBMED Abstract]
  9. Rowe JM, Andersen JW, Mazza JJ, et al.: A randomized placebo-controlled phase III study of granulocyte-macrophage colony-stimulating factor in adult patients (> 55 to 70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490). Blood 86 (2): 457-62, 1995. [PUBMED Abstract]
  10. Stone RM, Berg DT, George SL, et al.: Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. Cancer and Leukemia Group B. N Engl J Med 332 (25): 1671-7, 1995. [PUBMED Abstract]
  11. Dombret H, Chastang C, Fenaux P, et al.: A controlled study of recombinant human granulocyte colony-stimulating factor in elderly patients after treatment for acute myelogenous leukemia. AML Cooperative Study Group. N Engl J Med 332 (25): 1678-83, 1995. [PUBMED Abstract]
  12. Godwin JE, Kopecky KJ, Head DR, et al.: A double-blind placebo-controlled trial of granulocyte colony-stimulating factor in elderly patients with previously untreated acute myeloid leukemia: a Southwest oncology group study (9031). Blood 91 (10): 3607-15, 1998. [PUBMED Abstract]
  13. Buchner T, Hiddemann W, Wormann B, et al.: GM-CSF multiple course priming and long-term administration in newly diagnosed AML: hematologic and therapeutic effects. [Abstract] Blood 84 (10 Suppl 1): A-95, 27a, 1994.
  14. Löwenberg B, Boogaerts MA, Daenen SM, et al.: Value of different modalities of granulocyte-macrophage colony-stimulating factor applied during or after induction therapy of acute myeloid leukemia. J Clin Oncol 15 (12): 3496-506, 1997. [PUBMED Abstract]
  15. Witz F, Sadoun A, Perrin MC, et al.: A placebo-controlled study of recombinant human granulocyte-macrophage colony-stimulating factor administered during and after induction treatment for de novo acute myelogenous leukemia in elderly patients. Groupe Ouest Est Leucémies Aiguës Myéloblastiques (GOELAM). Blood 91 (8): 2722-30, 1998. [PUBMED Abstract]

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The Union of Biomarkers and Drug Development


The Union of Biomarkers and Drug Development

Author and Curator: Larry H. Bernstein, MD, FCAP

There has been consolidation going on for over a decade in both thr pharmaceutical and in the diagnostics industry, and at the same time the page is being rewritten for health care delivery.  I shall try to work through a clear picture of these not coincidental events.

Key notables:

  1. A growing segment of the US population is reaching Medicare age
  2. There is also a large underserved population in both metropolitan and nonurban areas and a fragmentation of the middle class after a growth slowdown in the economy since the 2008 deep recession.
  3. The deep recession affecting worldwide economies was only buffered by availability of oil or natural gas.
  4. In addition, there was a self-destructive strategy to cut spending on national scales that withdrew the support that would bolster support for infrastrucrue renewl.
  5. There has been a dramatic success in the clinical diagnostics industry, with a long history of being viewed as a loss leader, and this has been recently followed by the pharmaceutical industry faced with inability to introduce new products, leading to more competition in off-patent medications.
  6. The introduction of the Accountable Care Act has opened the opportunities for improved care, despite political opposition, and has probably sustained opportunity in the healthcare market.

Let’s take a look at this three headed serpent. – Pharma, Diagnostics, New Entity
?  The patient  ?
?  Insurance    ?
?  Physician    ?

Part I.   The Concept

When Illumina Buys Roche: The Dawning Of The Era Of Diagnostics Dominance

Robert J. Easton, Alain J. Gilbert, Olivier Lesueur, Rachel Laing, and Mark Ratner
http://PharmaMedtechBI.com    | IN VIVO: The Business & Medicine Report Jul/Aug 2014; 32(7).

  • With current technology and resources, a well-funded IVD company can create and pursue a strategy of information gathering and informatics application to create medical knowledge, enabling it to assume the risk and manage certain segments of patients
  • We see the first step in the process as the emergence of new specialty therapy companies coming from an IVD legacy, most likely focused in cancer, infection, or critical care

When Illumina Inc. acquired the regulatory consulting firm Myraqa, a specialist in in vitro diagnostics (IVD), in July, the press release announcement characterized the deal as one that would bolster illumina’s in-house capabilities for clinical readiness and help prepare for its next growth phase in regulated markets. That’s not surprising given the US Food and Drug Administration’s (FDA) approval a year and a half ago of its MiSeq next-generation sequencer for clinical use. But the deal could also suggest illumina is beginning to move along the path toward taking on clinical risk – that is, eventually

  • advising physicians and patients, which would mean facing regulators directly

Such a move – by illumina, another life sciences tools firm, or an information specialist from the high-tech universe – is inevitable given

  • the emerging power of diagnostics and traditional health care players’ reluctance to themselves take on such risk.

Alternatively, we believe that a well-funded diagnostics company could establish this position. either way, such a champion would establish dominion over and earn higher valuation than less-aggressive players who

  • only supply compartmentalized drug and device solutions.

Diagnostics companies have long been dogged by a fundamental issue:

  1. they are viewed and valued more along the lines of a commodity business than as firms that deliver a unique product or service
  2. diagnostics companies are in position to do just that today because they are now advantaged by having access to more data points.
  3. if they were to cobble together the right capabilities, diagnostics companies would have the ability to turn information into true medical knowledge

Example: PathGEN PathChip

nucleic-acid-based platform detects 296 viruses, bacteria, fungi & parasites

http://ow.ly/d/2GvQhttp://ow.ly/DSORV

This puts the diagnostics player in an unfamiliar realm where it can ask the question of what value they offer compared with a therapeutic. The key is that diagnostics can now offer unique information and potentially unique tools to capture that information. In order to do so, it has to create information from the data it generates, and then to supply that knowledge to users who will value and act on that knowledge. Complex genomic tests, as much as physical examination, may be the first meaningful touch point for physicians’ classification of disease.

Even if lab tests are more expensive, it is a cheaper means for deciding what to do first for a patient than the trial and error of prescribing medication without adequate information. Information is gaining in value as the amount of treatment data available on genomically characterizable subpopulations increases. In such a circumstance
it is the ability to perform that advisory function that will add tremendous value above what any test provides, the leverage of being able to apply a proprietary diagnostics platform – and importantly, the data it generates. It is the ability to perform that advisory function that will add tremendous value above what any test provides.

Integrated Diagnostics Inc. and Biodesix Inc. with mass spectrometry has the tools for unraveling disease processes, and numerous players are quite visibly in or are getting into the business of providing medical knowledge and clinical decision support in pursuit of a huge payout for those who actually solve important disease mysteries. Of course one has to ask whether MS/MS is sufficient for the assigned task, and also whether the technology is ready for the kind of workload experienced in a clinical service compared to a research vehicle.  My impression (as a reviewer) is that it is not now the time to take this seriously.

Roche has not realized its intent with Ventana: failing to deliver on the promise of boosting Roche’s pipeline, which was a significant factor in the high price Roche paid. The combined company was to be “uniquely positioned to further expand Ventana’s business globally and together develop more cost-efficient, differentiated, and targeted medicines.  On the other hand,  Biodesix decided to use Veristrat to look back and analyze important trial data to try to ascertain which patients would benefit from ficlatuzumab (subset). The predictive effect for the otherwise unimpressive trial results was observed in both progression-free survival and overall survival endpoints, and encouraged the companies to conduct a proof-of-concept study of ficlatuzumab in combination with Tarceva in advanced Non Small Cell Lung Cancer Patients (NSCLC) selected using the Veristrat test.

A second phase of IVD evolution will be far more challenging to pharma, when the most accomplished companies begin to assemble and integrate much broader data
sets, thereby gaining knowledge sufficient to actually manage patients and dictate therapy, including drug selection. No individual physician has or will have access to all of this information on thousands of patients, combined with the informatics to tease out from trillions of data points the optimal personalized medical approach. When the IVD-origin knowledge integrator amasses enough data and understanding to guide therapy decisions in large categories, particularly drug choices, it will become more valuable than any of the drug suppliers.

This is an apparent reversal of fortune. The pharmaceutical industry has been considered the valued provider, while the IVD manufacturer has been the low valued cousin. Now, it is by an ability to make kore accurate the drug administration that the IVD company can control the drug bill, to the detriment of drug developers, by finding algorithms that generate equal-to-innovative-drug outcomes using generics for most of the patients, thereby limiting the margins of drug suppliers and the upsides for new drug discovery/development.

It is here that there appears to be a misunderstanding of the whole picture of the development of the healthcare industry.  The pharmaceutical industry had a high value added only insofar it could replace market leaders for treatment before or at the time of patent expiration, which largely depended either introducing a new class of drug, or by relieving the current drug in its class of undesired toxicities or “side effects”.  Otherwise, the drug armamentarium was time limited to the expiration date. In other words, the value was dependent on a window of no competition.  In addition, as the regulation of healthcare costs were tightening under managed care, the introduction of new products that were deemed to be only marginally better, could be substitued by “off-patent” drug products.

The other misunderstanding is related to the IVD sector.  Laboratory tests in the 1950’s were manual, and they could be done by “technicians” who might not have completed a specialized training in clinical laboratory sciences.  The first sign of progress was the introduction of continuous flow chemistry, with a sampling probe, tubing to bring the reacting reagents into a photocell, and the timing of the reaction controlled by a coiled glass tubing before introducing the colored product into a uv-visible photometer.  In perhaps a decade, the Technicon SMA 12 and 6 instruments were introduced that could do up to 18 tests from a single sample.

Part 2. Emergence of an IVD Clinical Automated Diagnostics Industry

Why tests are ordered

  1. Screening
  2. Diagnosis
  3. Monitoring

Historical Perspective

Case in Point 1:  Outstanding Contributions in Clinical Chemistry. 1991. Arthur Karmen.

Dr. Karmen was born in New York City in 1930. He graduated from the Bronx High School of Science in 1946 and earned an A.B. and M.D. in 1950 and 1954, respectively, from New York University. In 1952, while a medical student working on a summer project at Memorial-Sloan Kettering, he used paper chromatography of amino acids to demonstrate the presence of glutamic-oxaloacetic and glutaniic-pyruvic ransaminases (aspartate and alanine aminotransferases) in serum and blood. In 1954, he devised the spectrophotometric method for measuring aspartate aminotransferase in serum, which, with minor modifications, is still used for diagnostic testing today. When developing this assay, he studied the reaction of NADH with serum and demonstrated the presence of lactate and malate dehydrogenases, both of which were also later used in diagnosis. Using the spectrophotometric method, he found that aspartate aminotransferase increased in the period immediately after an acute myocardial infarction and did the pilot studies that showed its diagnostic utility in heart and liver diseases.  This became as important as the EKG. It was replaced in cardiology usage by the MB isoenzyme of creatine kinase, which was driven by Burton Sobel’s work on infarct size, and later by the troponins.

Case in point 2: Arterial Blood Gases.  Van Slyke. National Academy of Sciences.

The test is used to determine the pH of the blood, the partial pressure of carbon dioxide and oxygen, and the bicarbonate level. Many blood gas analyzers will also report concentrations of lactate, hemoglobin, several electrolytes, oxyhemoglobin, carboxyhemoglobin and methemoglobin. ABG testing is mainly used in pulmonology and critical care medicine to determine gas exchange which reflect gas exchange across the alveolar-capillary membrane.

DONALD DEXTER VAN SLYKE died on May 4, 1971, after a long and productive career that spanned three generations of biochemists and physicians. He left behind not only a bibliography of 317 journal publications and 5 books, but also more than 100 persons who had worked with him and distinguished themselves in biochemistry and academic medicine. His doctoral thesis, with Gomberg at University of Michigan was published in the Journal of the American Chemical Society in 1907.  Van Slyke received an invitation from Dr. Simon Flexner, Director of the Rockefeller Institute, to come to New York for an interview. In 1911 he spent a year in Berlin with Emil Fischer, who was then the leading chemist of the scientific world. He was particularly impressed by Fischer’s performing all laboratory operations quantitatively —a procedure Van followed throughout his life. Prior to going to Berlin, he published the  classic nitrous acid method for the quantitative determination of primary aliphatic amino groups,  the first of the many gasometric procedures devised by Van Slyke, and made possible the determination of amino acids. It was the primary method used to study amino acid

composition of proteins for years before chromatography. Thus, his first seven postdoctoral years were centered around the development of better methodology for protein composition and amino acid metabolism.

With his colleague G. M. Meyer, he first demonstrated that amino acids, liberated during digestion in the intestine, are absorbed into the bloodstream, that they are removed by the tissues, and that the liver alone possesses the ability to convert the amino acid nitrogen into urea.  From the study of the kinetics of urease action, Van Slyke and Cullen developed equations that depended upon two reactions: (1) the combination of enzyme and substrate in stoichiometric proportions and (2) the reaction of the combination into the end products. Published in 1914, this formulation, involving two velocity constants, was similar to that arrived at contemporaneously by Michaelis and Menten in Germany in 1913.

He transferred to the Rockefeller Institute’s Hospital in 2013, under Dr. Rufus Cole, where “Men who were studying disease clinically had the right to go as deeply into its fundamental nature as their training allowed, and in the Rockefeller Institute’s Hospital every man who was caring for patients should also be engaged in more fundamental study”.  The study of diabetes was already under way by Dr. F. M. Allen, but patients inevitably died of acidosis.  Van Slyke reasoned that if incomplete oxidation of fatty acids in the body led to the accumulation of acetoacetic and beta-hydroxybutyric acids in the blood, then a reaction would result between these acids and the bicarbonate ions that would lead to a lower than-normal bicarbonate concentration in blood plasma. The problem thus became one of devising an analytical method that would permit the quantitative determination of bicarbonate concentration in small amounts of blood plasma.  He ingeniously devised a volumetric glass apparatus that was easy to use and required less than ten minutes for the determination of the total carbon dioxide in one cubic centimeter of plasma.  It also was soon found to be an excellent apparatus by which to determine blood oxygen concentrations, thus leading to measurements of the percentage saturation of blood hemoglobin with oxygen. This found extensive application in the study of respiratory diseases, such as pneumonia and tuberculosis. It also led to the quantitative study of cyanosis and a monograph on the subject by C. Lundsgaard and Van Slyke.

In all, Van Slyke and his colleagues published twenty-one papers under the general title “Studies of Acidosis,” beginning in 1917 and ending in 1934. They included not only chemical manifestations of acidosis, but Van Slyke, in No. 17 of the series (1921), elaborated and expanded the subject to describe in chemical terms the normal and abnormal variations in the acid-base balance of the blood. This was a landmark in understanding acid-base balance pathology.  Within seven years after Van moved to the Hospital, he had published a total of fifty-three papers, thirty-three of them coauthored with clinical colleagues.

In 1920, Van Slyke and his colleagues undertook a comprehensive investigation of gas and electrolyte equilibria in blood. McLean and Henderson at Harvard had made preliminary studies of blood as a physico-chemical system, but realized that Van Slyke and his colleagues at the Rockefeller Hospital had superior techniques and the facilities necessary for such an undertaking. A collaboration thereupon began between the two laboratories, which resulted in rapid progress toward an exact physico-chemical description of the role of hemoglobin in the transport of oxygen and carbon dioxide, of the distribution of diffusible ions and water between erythrocytes and plasma,
and of factors such as degree of oxygenation of hemoglobin and hydrogen ion concentration that modified these distributions. In this Van Slyke revised his volumetric gas analysis apparatus into a manometric method.  The manometric apparatus proved to give results that were from five to ten times more accurate.

A series of papers on the CO2 titration curves of oxy- and deoxyhemoglobin, of oxygenated and reduced whole blood, and of blood subjected to different degrees of oxygenation and on the distribution of diffusible ions in blood resulted.  These developed equations that predicted the change in distribution of water and diffusible ions between blood plasma and blood cells when there was a change in pH of the oxygenated blood. A significant contribution of Van Slyke and his colleagues was the application of the Gibbs-Donnan Law to the blood—regarded as a two-phase system, in which one phase (the erythrocytes) contained a high concentration of nondiffusible negative ions, i.e., those associated with hemoglobin, and cations, which were not freely exchaThe importance of Vanngeable between cells and plasma. By changing the pH through varying the CO2 tension, the concentration of negative hemoglobin charges changed in a predictable amount. This, in turn, changed the distribution of diffusible anions such as Cl” and HCO3″ in order to restore the Gibbs-Donnan equilibrium. Redistribution of water occurred to restore osmotic equilibrium. The experimental results confirmed the predictions of the equations.

As a spin-off from the physico-chemical study of the blood, Van undertook, in 1922, to put the concept of buffer value of weak electrolytes on a mathematically exact basis.
This proved to be useful in determining buffer values of mixed, polyvalent, and amphoteric electrolytes, and put the understanding of buffering on a quantitative basis. A
monograph in Medicine entitled “Observation on the Courses of Different Types of Bright’s Disease, and on the Resultant Changes in Renal Anatomy,” was a landmark that
related the changes occurring at different stages of renal deterioration to the quantitative changes taking place in kidney function. During this period, Van Slyke and R. M. Archibald identified glutamine as the source of urinary ammonia. During World War II, Van and his colleagues documented the effect of shock on renal function and, with R. A. Phillips, developed a simple method, based on specific gravity, suitable for use in the field.

Over 100 of Van’s 300 publications were devoted to methodology. The importance of Van Slyke’s contribution to clinical chemical methodology cannot be overestimated.
These included the blood organic constituents (carbohydrates, fats, proteins, amino acids, urea, nonprotein nitrogen, and phospholipids) and the inorganic constituents (total cations, calcium, chlorides, phosphate, and the gases carbon dioxide, carbon monoxide, and nitrogen). It was said that a Van Slyke manometric apparatus was almost all the special equipment needed to perform most of the clinical chemical analyses customarily performed prior to the introduction of photocolorimeters and spectrophotometers for such determinations.

The progress made in the medical sciences in genetics, immunology, endocrinology, and antibiotics during the second half of the twentieth century obscures at times the progress that was made in basic and necessary biochemical knowledge during the first half. Methods capable of giving accurate quantitative chemical information on biological material had to be painstakingly devised; basic questions on chemical behavior and metabolism had to be answered; and, finally, those factors that adversely modified the normal chemical reactions in the body so that abnormal conditions arise that we characterize as disease states had to be identified.

Viewed in retrospect, he combined in one scientific lifetime (1) basic contributions to the chemistry of body constituents and their chemical behavior in the body, (2) a chemical understanding of physiological functions of certain organ systems (notably the respiratory and renal), and (3) how such information could be exploited in the
understanding and treatment of disease. That outstanding additions to knowledge in all three categories were possible was in large measure due to his sound and broadly based chemical preparation, his ingenuity in devising means of accurate measurements of chemical constituents, and the opportunity given him at the Hospital of the Rockefeller Institute to study disease in company with physicians.

In addition, he found time to work collaboratively with Dr. John P. Peters of Yale on the classic, two-volume Quantitative Clinical Chemistry. In 1922, John P. Peters, who had just gone to Yale from Van Slyke’s laboratory as an Associate Professor of Medicine, was asked by a publisher to write a modest handbook for clinicians describing useful chemical methods and discussing their application to clinical problems. It was originally to be called “Quantitative Chemistry in Clinical Medicine.” He soon found that it was going to be a bigger job than he could handle alone and asked Van Slyke to join him in writing it. Van agreed, and the two men proceeded to draw up an outline and divide up the writing of the first drafts of the chapters between them. They also agreed to exchange each chapter until it met the satisfaction of both.At the time it was published in 1931, it contained practically all that could be stated with confidence about those aspects of disease that could be and had been studied by chemical means. It was widely accepted throughout the medical world as the “Bible” of quantitative clinical chemistry, and to this day some of the chapters have not become outdated.

History of Laboratory Medicine at Yale University.

The roots of the Department of Laboratory Medicine at Yale can be traced back to John Peters, the head of what he called the “Chemical Division” of the Department of Internal Medicine, subsequently known as the Section of Metabolism, who co-authored with Donald Van Slyke the landmark 1931 textbook Quantitative Clinical Chemistry (2.3); and to Pauline Hald, research collaborator of Dr. Peters who subsequently served as Director of Clinical Chemistry at Yale-New Haven Hospital for many years. In 1947, Miss Hald reported the very first flame photometric measurements of sodium and potassium in serum (4). This study helped to lay the foundation for modern studies of metabolism and their application to clinical care.

The Laboratory Medicine program at Yale had its inception in 1958 as a section of Internal Medicine under the leadership of David Seligson. In 1965, Laboratory Medicine achieved autonomous section status and in 1971, became a full-fledged academic department. Dr. Seligson, who served as the first Chair, pioneered modern automation and computerized data processing in the clinical laboratory. In particular, he demonstrated the feasibility of discrete sample handling for automation that is now the basis of virtually all automated chemistry analyzers. In addition, Seligson and Zetner demonstrated the first clinical use of atomic absorption spectrophotometry. He was one of the founding members of the major Laboratory Medicine academic society, the Academy of Clinical Laboratory Physicians and Scientists.

Davenport fig 10.jpg

Case in Point 3.  Nathan Gochman.  Developer of Automated Chemistries.

Nathan Gochman, PhD, has over 40 years of experience in the clinical diagnostics industry. This includes academic teaching and research, and 30 years in the pharmaceutical and in vitro diagnostics industry. He has managed R & D, technical marketing and technical support departments. As a leader in the industry he was President of the American Association for Clinical Chemistry (AACC) and the National Committee for Clinical Laboratory Standards (NCCLS, now CLSI). He is currently a Consultant to investment firms and IVD companies.

Nathan Gochman

Nathan Gochman

The clinical laboratory has become so productive, particularly in chemistry and immunology, and the labor, instrument and reagent costs are well determined, that today a physician’s medical decisions are 80% determined by the clinical laboratory.  Medical information systems have lagged far behind.  Why is that?  Because the decision for a MIS has historical been based on billing capture.  Moreover, the historical use of chemical profiles were quite good at validating healthy dtatus in an outpatient population, but the profiles became restricted under Diagnostic Related Groups.    Thus, it came to be that the diagnostics was considered a “commodity”.  In order to be competitive, a laboratory had to provide “high complexity” tests that were drawn in by a large volume of “moderate complexity”tests.

Part 3. Biomarkers in Medical Practice

Case in Point 1.

A Solid Prognostic Biomarker

HDL-C: Target of Therapy or Fuggedaboutit?

Steven E. Nissen, MD, MACC, Peter Libby, MD

DisclosuresNovember 06, 2014

Steven E. Nissen, MD, MACC: I am Steve Nissen, chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic. I am here with Dr Peter Libby, chief of cardiology at the Brigham and Women’s Hospital and professor of medicine at Harvard Medical School. We are going to discuss high-density lipoprotein cholesterol (HDL-C), a topic that has been very controversial recently. Peter, HDL-C has been a pretty good biomarker. The question is whether it is a good target.

Peter Libby, MD: Since the early days in Berkley, when they were doing ultracentrifugation, and when it was reinforced and put on the map by the Framingham Study,[1] we have known that HDL-C is an extremely good biomarker of prospective cardiovascular risk with an inverse relationship with all kinds of cardiovascular events. That is as solid a finding as you can get in observational epidemiology. It is a very reliable prospective marker. It’s natural that the pharmaceutical industry and those of us who are interested in risk reduction would focus on HDL-C as a target. That is where the controversies come in.

Dr Nissen: It has been difficult. My view is that the trials that have attempted to modulate HDL-C or the drugs they used have been flawed. Although the results have not been promising, the jury is yet out. Torcetrapib, the cholesteryl ester transfer protein (CETP) inhibitor developed by Pfizer, had anoff-target toxicity.[2] Niacin is not very effective, and there are a lot of downsides to the drug. That has been an issue, but people are still working on this. We have done some studies. We did our ApoA-1 Milano infusion study[3]about a decade ago, which showed very promising results with respect to shrinking plaques in coronary arteries. I remain open to the possibility that the right drug in the right trial will work.

Dr Libby: What do you do with the genetic data that have come out in the past couple of years? Sekar Kathiresan masterminded and organized an enormous collaboration[4] in which they looked, with contemporary genetics, at whether HDL had the genetic markers of being a causal risk factor. They came up empty-handed.

Dr Nissen: I am cautious about interpreting those data, like I am cautious about interpreting animal studies of atherosclerosis. We have both lived through this problem in which something works extremely well in animals but doesn’t work in humans, or it doesn’t work in animals but it works in humans. The genetic studies don’t seal the fate of HDL. I have an open mind about this. Drugs are complex. They work by complex mechanisms. It is my belief that what we have to do is test these hypotheses in well-designed clinical trials, which are rigorously performed with drugs that are clean—unlike torcetrapib—and don’t have off-target toxicities.

An Unmet Need: High Lp(a) Levels

Dr Nissen: I’m going to push back on that and make a couple of points. The HPS2-THRIVE study was flawed. They studied the wrong people. It was not a good study, and AIM-HIGH[8] was underpowered. I am not putting people on niacin. What do you do with a patient whose Lp(a) is 200 mg/dL?

Dr Libby: I’m waiting for the results of the PCSK9 and anacetrapib studies. You can tell me about evacetrapib.[9]Reducing Lp(a) is an unmet medical need. We both care for kindreds with high Lp(a) levels and premature coronary artery disease. We have no idea what to do with them other than to treat them with statins and lower their LDL-C levels.

Dr Nissen: I have taken a more cautious approach with respect to taking people off of niacin. If I have patients who are doing well and tolerating it (depending on why it was started), I am discontinuing niacin in some people. I am starting very few people on the drug, but I worry about the quality of the trial.

Dr Libby: So you are of the “don’t start don’t stop” school?

Dr Nissen: Yes. It’s difficult when the trial is fatally flawed. There were 11,000 patients from China in this study. I have known for years that if you give niacin to people of Asiatic ethnic descent, they have terrible flushing and they won’t continue the drug. One question is, what was the adherence? The adverse events would have been tolerable had there been efficacy. The concern here is that this study was destined to fail because they studied a low LDL/high HDL population, a group of people for whom niacin just isn’t used.

Triglycerides and HDL: Do We Have It Backwards?

Dr Libby: What about the recent genetic[10] and epidemiologic data that support triglycerides, and apolipoprotein C3 in particular as a causal risk factor? Have we been misled through all of the generations in whom we have been adjusting triglycerides for HDL-C and saying that triglycerides are not a causal risk factor because once we adjust for HDL, the risk goes away? Do you think we got it backwards?

Dr Nissen: The tricky factor here is that because of this intimate inverse relationship between triglycerides and HDL, we may be talking about the same phenomenon. That is one of the reasons that I am not certain we are not going to be able to find a therapy. What if you had a therapy that lowered triglycerides and raised HDL-C? Could that work? Could that combination be favorable? I want answers from rigorous, well-designed clinical trials that ask the right questions in the right populations. I am disappointed, just as I have been disappointed by the fibrate trials.[11,12] There is a class of drugs that raises HDL-C a little and lowers triglycerides a lot.

Dr Nissen: But the gemfibrozil studies (VA-HIT[13] and Helsinki Heart[14]) showed benefit.

The Dyslipidemia Bar Has Been Raised

Dr Libby: Those studies were from the pre-statin era. We both were involved in trials in which patients were on high-dose statins at baseline. Do you think that this is too high a bar?

Dr Nissen: The bar has been raised, and for the pharmaceutical industry, the studies that we need to find out whether lowering triglycerides or raising HDL is beneficial are going to be large. We are doing a study with evacetrapib. It has 12,000 patients. It’s fully enrolled. Evacetrapib is a very clean-looking drug. It doesn’t have such a long biological half-life as anacetrapib, so I am very encouraged that it won’t have that baggage of being around for 2-4 years. We’ve got a couple of shots on goal here. Don’t forget that we have multiple ongoing studies of HDL-C infusion therapies that are still under development. Those have some promise too. The jury is still out.

Dr Libby: We agree on the need to do rigorous, large-scale endpoint trials. Do the biomarker studies, but don’t wait to start the endpoint trial because that’s the proof in the pudding.

Dr Nissen: Exactly. We have had a little controversy about HDL-C. We often agree, but not always, and we may have a different perspective. Thanks for joining me in this interesting discussion of what will continue to be a controversial topic for the next several years until we get the results of the current ongoing trials.

Case in Point 2.

NSTEMI? Honesty in Coding and Communication?

Melissa Walton-Shirley

November 07, 2014

The complaint at ER triage: Weakness, fatigue, near syncope of several days’ duration, vomiting, and decreased sensorium.

The findings: O2sat: 88% on room air. BP: 88 systolic. Telemetry: Sinus tachycardia 120 bpm. Blood sugar: 500 mg/dL. Chest X ray: atelectasis. Urinalysis: pyuria. ECG: T-wave-inversion anterior leads. Echocardiography: normal left ventricular ejection fraction (LVEF) and wall motion. Troponin I: 0.3 ng/mL. CT angiography: negative for pulmonary embolism (PE). White blood cell count: 20K with left shift. Blood cultures: positive for Gram-negative rods.

The treatment: Intravenous fluids and IV levofloxacin—changed to ciprofloxacin.

The communication at discharge: “You had a severe urinary-tract infection and grew bacteria in your bloodstream. Also, you’ve had a slight heart attack. See your cardiologist immediately upon discharge-no more than 5 days from now.”

The diagnoses coded at discharge: Urosepsis and non-ST segment elevation MI (NSTEMI) 410.1.

One year earlier: This moderately obese patient was referred to our practice for a preoperative risk assessment. The surgery planned was a technically simple procedure, but due to the need for precise instrumentation, general endotracheal anesthesia (GETA) was being considered. The patient was diabetic, overweight, and short of air. A stress exam was equivocal for CAD due to poor exercise tolerance and suboptimal imaging. Upon further discussion, symptoms were progressive; therefore, cardiac cath was recommended, revealing angiographically normal coronaries and a predictably elevated left ventricular end diastolic pressure (LVEDP) in the mid-20s range. The patient was given a diagnosis of diastolic dysfunction, a prescription for better hypertension control, and in-depth discussion on exercise and the Mediterranean and DASH diets for weight loss. Symptoms improved with a low dose of diuretic. The surgery was completed without difficulty. Upon follow-up visit, the patient felt well, had lost a few pounds, and blood pressure was well controlled.

Five days after ER workup: While out of town, the patient developed profound weakness and went to the ER as described above. Fast forward to our office visit in the designated time frame of “no longer than 5 days’ postdischarge,” where the patient and family asked me about the “slight heart attack” that literally came on the heels of a normal coronary angiogram.

But the patient really didn’t have a “heart attack,” did they? The cardiologist aptly stated that it was likely nonspecific troponin I leak in his progress notes. Yet the hospitalist framed the diagnosis of NSTEMI as item number 2 in the final diagnoses.

The motivations on behalf of personnel who code charts are largely innocent and likely a direct result of the lack of understanding of the coding system on behalf of us as healthcare providers. I have a feeling, though, that hospitals aren’t anxious to correct this misperception, due to an opportunity for increased reimbursement. I contacted a director of a coding department for a large hospital who prefers to remain anonymous. She explained that NSTEMI ICD9 code 410.1 falls in DRG 282 with a weight of .7562. The diagnosis of “demand ischemia,” code 411.89, a slightly less inappropriate code for a nonspecific troponin I leak, falls in DRG 311 with a weight of .5662. To determine reimbursement, one must multiply the weight by the average hospital Medicare base rate of $5370. Keep in mind that each hospital’s base rate and corresponding payment will vary. The difference in reimbursement for a large hospital bill between these two choices for coding is substantial, at over $1000 difference ($4060 vs $3040).

Although hospitals that are already reeling from shrinking revenues will make more money on the front end by coding the troponin leak incorrectly as an NSTEMI, when multiple unnecessary tests are generated to follow up on a nondiagnostic troponin leak, the amount of available Centers for Medicare & Medicaid Services (CMS) reimbursement pie shrinks in the long run. Furthermore, this inappropriate categorization generates extreme concern on behalf of patients and family members that is often never laid to rest. The emotional toll of a “heart-attack” diagnosis has an impact on work fitness, quality of life, cost of medication, and the cost of future testing. If the patient lived for another 100 years, they will likely still list a “heart attack” in their medical history.

As a cardiologist, I resent the loose utilization of one of “my” heart-attack codes when it wasn’t that at all. At discharge, we need to develop a better way of communicating what exactly did happen. Equally important, we need to communicate what exactly didn’t happen as well.

Case in Point 3.

Blood Markers Predict CKD Heart Failure 

Published: Oct 3, 2014 | Updated: Oct 3, 2014

Elevated levels of high-sensitivity troponin T (hsTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) strongly predicted heart failure in patients with chronic kidney disease followed for a median of close to 6 years, researchers reported.

Compared with patients with the lowest blood levels of hsTnT, those with the highest had a nearly five-fold higher risk for developing heart failure and the risk was 10-fold higher in patients with the highest NT-proBNP levels compared with those with the lowest levels of the protein, researcher Nisha Bansal, MD, of the University of Washington in Seattle, and colleagues wrote online in the Journal of the American Society of Nephrology.

A separate study, published online in theJournal of the American Medical Association earlier in the week, also examined the comorbid conditions of heart and kidney disease, finding no benefit to the practice of treating cardiac surgery patients who developed acute kidney injury with infusions of the antihypertensive drug fenoldopam.

The study, reported by researcher Giovanni Landoni, MD, of the IRCCS San Raffaele Scientific Institute, Milan, Italy, and colleagues, was stopped early “for futility,” according to the authors, and the incidence of hypotension during drug infusion was significantly higher in patients infused with fenoldopam than placebo (26% vs. 15%; P=0.001).

Blood Markers Predict CKD Heart Failure

The study in patients with mild to moderate chronic kidney disease (CKD) was conducted to determine if blood markers could help identify patients at high risk for developing heart failure.

Heart failure is the most common cardiovascular complication among people with renal disease, occurring in about a quarter of CKD patients.

The two markers, hsTnT and NT-proBNP, are associated with overworked cardiac myocytes and have been shown to predict heart failure in the general population.

However, Bansal and colleagues noted, the markers have not been widely used in diagnosing heart failure among patients with CKD due to concerns that reduced renal excretion may raise levels of these markers, and therefore do not reflect an actual increase in heart muscle strain.

To better understand the importance of elevated concentrations of hsTnT and NT-proBNP in CKD patients, the researchers examined their association with incident heart failure events in 3,483 participants in the ongoing observational Chronic Renal Insufficiency Cohort (CRIC) study.

All participants were recruited from June 2003 to August 2008, and all were free of heart failure at baseline. The researchers used Cox regression to examine the association of baseline levels of hsTnT and NT-proBNP with incident heart failure after adjustment for demographic influences, traditional cardiovascular risk factors, makers of kidney disease, pertinent medication use, and mineral metabolism markers.

At baseline, hsTnT levels ranged from ≤5.0 to 378.7 pg/mL and NT-proBNP levels ranged from ≤5 to 35,000 pg/mL. Compared with patients who had undetectable hsTnT, those in the highest quartile (>26.5 ng/mL) had a significantly higher rate of heart failure (hazard ratio 4.77; 95% CI 2.49-9.14).

Compared with those in the lowest NT-proBNP quintile (<47.6 ng/mL), patients in the highest quintile (>433.0 ng/mL) experienced an almost 10-fold increase in heart failure risk (HR 9.57; 95% CI 4.40-20.83).

The researchers noted that these associations remained robust after adjustment for potential confounders and for the other biomarker, suggesting that while hsTnT and NT-proBNP are complementary, they may be indicative of distinct biological pathways for heart failure.

Even Modest Increases in NP-proBNP Linked to Heart Failure

The findings are consistent with an earlier analysis that included 8,000 patients with albuminuria in the Prevention of REnal and Vascular ENd-stage Disease (PREVEND) study, which showed that hsTnT was associated with incident cardiovascular events, even after adjustment for eGFR and severity of albuminuria.

“Among participants in the CRIC study, those with the highest quartile of detectable hsTnT had a twofold higher odds of left ventricular hypertrophy compared with those in the lowest quartile,” Bansal and colleagues wrote, adding that the findings were similar after excluding participants with any cardiovascular disease at baseline.

Even modest elevations in NT-proBNP were associated with significantly increased rates of heart failure, including in subgroups stratified by eGFR, proteinuria, and diabetic status.

“NT-proBNP regulates blood pressure and body fluid volume by its natriuretic and diuretic actions, arterial dilation, and inhibition of the renin-aldosterone-angiotensin system and increased levels of this marker likely reflect myocardial stress induced by subclinical changes in volume or pressure, even in persons without clinical disease,” the researchers wrote.

The researchers concluded that further studies are needed to develop and validate risk prediction tools for clinical heart failure in patients with CKD, and to determine the potential role of these two biomarkers in a heart failure risk prediction and prevention strategy.

Fenoldopam ‘Widely Promoted’ in AKI Cardiac Surgery Setting

The JAMA study examined whether the selective dopamine receptor D agonist fenoldopam mesylate can reduce the need for dialysis in cardiac surgery patients who develop acute kidney injury (AKI).

Fenoldopam induces vasodilation of the renal, mesenteric, peripheral, and coronary arteries, and, unlike dopamine, it has no significant affinity for D2 receptors, meaning that it theoretically induces greater vasodilation in the renal medulla than in the cortex, the researchers wrote.

“Because of these hemodynamic effects, fenoldopam has been widely promoted for the prevention and therapy of AKI in the United States and many other countries with apparent favorable results in cardiac surgery and other settings,” Landoni and colleagues wrote.

The drug was approved in 1997 by the FDA for the indication of in-hospital, short-term management of severe hypertension. It has not been approved for renal indications, but is commonly used off-label in cardiac surgery patients who develop AKI.

Although a meta analysis of randomized trials, conducted by the researchers, indicated a reduction in the incidence and progression of AKI associated with the treatment, Landoni and colleagues wrote that the absence of a definitive trial “leaves clinicians uncertain as to whether fenoldopam should be prescribed after cardiac surgery to prevent deterioration in renal function.”

To address this uncertainty, the researchers conducted a prospective, randomized, parallel-group trial in 667 patients treated at 19 hospitals in Italy from March 2008 to April 2013.

All patients had been admitted to ICUs after cardiac surgery with early acute kidney injury (≥50% increase of serum creatinine level from baseline or low output of urine for ≥6 hours). A total of 338 received fenoldopam by continuous intravenous infusion for a total of 96 hours or until ICU discharge, while 329 patients received saline infusions.

The primary end point was the rate of renal replacement therapy, and secondary end points included mortality (intensive care unit and 30-day mortality) and the rate of hypotension during study drug infusion.

Study Showed No Benefit, Was Stopped Early

Yale Lampoon – AA Liebow.   1954

Not As a Doctor
[Fourth Year]

These lyrics, sung by John Cole, Jack Gariepy and Ed Ransenhofer to music borrowed from Gilbert and Sullivan’s The Mikado, lampooned Averill Liebow, M.D., a pathologist noted for his demands on students. (CPC stands for clinical pathology conference.)

If you want to know what this is,
it’s a medical CPC
Where we give the house staff
the biz, for there’s no one so
wise as we!
We pathologists show them how,
Although it is too late now.
Our art is a sacred cow!

American physician, born 1911, Stryj in Galicia, Austria (now in Ukraine); died 1978.

Averill Abraham Liebow, born in Austria, was the “founding father” of pulmonary pathology in the United States. He started his career as a pathologist at Yale, where he remained for many years. In 1968 he moved to the University of California School of Medicine, San Diego, where he taught for 7 years as Professor and Chairman, Department of Pathology.

His studies include many classic studies of lung diseases. Best known of these is his famous classification of interstitial lung disease. He also published papers on sclerosing pneumocytoma, pulmonary alveolar proteinosis, meningothelial-like nodules, pulmonary hypertension, pulmonary veno-occlusive disease, lymphomatoid granulomatosis, pulmonary Langerhans cell histiocytosis, pulmonary epithelioid hemangioendothelioma and pulmonary hyalinizing granuloma .

As a Lieutenant Colonel in the US Army Medical Corps, He was a member of the Atomic Bomb Casualty Commission who studied the effects of the atomic bomb in Hiroshima and Nagasaki.

We thank Sanjay Mukhopadhyay, M.D., for information submitted.

As a resident at UCSD, Dr. Liebow held “Organ Recitals” every morning, including Mother’s day.  The organs had to be presented in specified order… heart, lung, and so forth.  On one occasion, we needed a heart for purification of human lactate dehydrogenase for a medical student project, so I presented the lung out of order.  Dr. Liebow asked where the heart was, and I told the group it was noprmal and I froze it for enzyme purification (smiles).  In the future show it to me first. He was generous to those who showed interest.  As I was also doing research in Nathan Kaplan’s laboratory, he made special arrangements for me to mentor Deborah Peters, the daughter of a pulmonary physician, and granddaughter of the Peters who collaborated with Van Slyke.  I mentored many students with great reward since then.  He could look at a slide and tell you what the x-ray looked like.  I didn’t encounter that again until he sent me to the Armed Forces Institute of Pathology, Washington, DC during the Vietnam War and Watergate, and I worked in Orthopedic Pathology with Lent C. Johnson.  He would not review a case without the x-ray, and he taught the radiologists.

Part 3

My Cancer Genome from Vanderbilt University: Matching Tumor Mutations to Therapies & Clinical Trials

Reporter: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2014/11/05/my-cancer-genome-from-vanderbilt-university-matching-tumor-mutations-to-therapies-clinical-trials/

GenomOncology and Vanderbilt-Ingram Cancer Center (VICC) today announced a partnership for the exclusive commercial development of a decision support tool based on My Cancer Genome™, an online precision cancer medicine knowledge resource for physicians, patients, caregivers and researchers.

Through this collaboration, GenomOncology and VICC will enhance My Cancer Genome through the development of a new genomics content management tool. The MyCancerGenome.org website will remain free and open to the public. In addition, GenomOncology will develop a decision support tool based on My Cancer Genome™ data that will enable automated interpretation of mutations in the genome of a patient’s tumor, providing actionable results in hours versus days.

Vanderbilt-Ingram Cancer Center (VICC) launched My Cancer Genome™ in January 2011 as an integral part of their Personalized Cancer Medicine Initiative that helps physicians and researchers track the latest developments in precision cancer medicine and connect with clinical research trials. This web-based information tool is designed to quickly educate clinicians on the rapidly expanding list of genetic mutations that impact cancers and enable the research of treatment options based on specific mutations. For more information on My Cancer Genome™visit www.mycancergenome.org/about/what-is-my-cancer-genome.

Therapies based on the specific genetic alterations that underlie a patient’s cancer not only result in better outcomes but often have less adverse reactions

Up front fee

Nominal fee covers installation support, configuring the Workbench to your specification, designing and developing custom report(s) and training your team.

Per sample fee

GenomOncology is paid on signed-out clinical reports. This philosophy aligns GenomOncology with your Laboratory as we are incentivized to offer world-class support and solutions to differentiate your clinical NGS program. There is no annual license fee.

Part 4

Clinical Trial Services: Foundation Medicine & EmergingMed to Partner

Reporter: Aviva Lev-Ari, PhD, RN
https://pharmaceuticalintelligence.com/2014/11/03/clinical-trial-services-foundation-medicine-emergingmed-to-partner/

Foundation Medicine and EmergingMed said today that they will partner to offer clinical trial navigation services for health care providers and their patients who have received one of Foundation Medicine’s tumor genomic profiling tests.

The firms will provide concierge services to help physicians

  • identify appropriate clinical trials for patients
  • based on the results of FoundationOne or FoundationOne Heme.

“By providing clinical trial navigation services, we aim to facilitate

  • timely and accurate clinical trial information and enrollment support services for physicians and patients,
  • enabling greater access to treatment options based on the unique genomic profile of a patient’s cancer

Currently, there are over 800 candidate therapies that target genomic alterations in clinical trials,

  • but “patients and physicians must identify and act on relevant options
  • when the patient’s clinical profile is aligned with the often short enrollment window for each trial.

These investigational therapies are an opportunity to engage patients with cancer whose cancer has progressed or returned following standard treatment in a most favorable second option after relapse.  The new service is unique in notifying when new clinical trials emerge that match a patient’s genomic and clinical profile.

Google signs on to Foundation Medicine cancer Dx by offering tests to employees

By Emily Wasserman

Diagnostics luminary Foundation Medicine ($FMI) is generating some upward momentum, fueled by growing revenues and the success of its clinical tests. Tech giant Google ($GOOG) has taken note and is signing onto the company’s cancer diagnostics by offering them to employees.

Foundation Medicine CEO Michael Pellini said during the company’s Q3 earnings call that Google will start covering its DNA tests for employees and their family members suffering from cancer as part of its health benefits portfolio, Reuters reports.

Both sides stand to benefit from the deal, as Google looks to keep a leg up on Silicon Valley competitors and Foundation Medicine expands its cancer diagnostics platform. Last month, Apple ($AAPL) and Facebook ($FB) announced that they would begin covering the cost of egg freezing for female employees. A diagnostics partnership and attractive health benefits could work wonders for Google’s employee retention rates and bottom line.

In the meantime, Cambridge, MA-based Foundation Medicine is charging full speed ahead with its cancer diagnostics platform after filing for an IPO in September 2013. The company chalked up 6,428 clinical tests during Q3 2014, an eye-popping 149% increase year over year, and brought in total revenue for the quarter of $16.4 million–a 100% leap from last year. Foundation Medicine credits the promising numbers in part to new diagnostic partnerships and extended coverage for its tests.

In January, the company teamed up with Novartis ($NVS) to help the drugmaker evaluate potential candidates for its cancer therapies. In April, Foundation Medicine announced that it would develop a companion diagnostic test for a Clovis Oncology ($CLVS) drug under development to treat patients with ovarian cancer, building on an ongoing collaboration between the two companies.

Foundation Medicine also has its sights set on China’s growing diagnostics market, inking a deal in October with WuXi PharmaTech ($WX) that allows the company to perform lab testing for its FoundationOne assay at WuXi’s Shanghai-based Genome Center.

a nod to the deal with Google during a corporate earnings call on Wednesday, according to a person who listened in. Pellini said Google employees were made aware of this new benefit last week.

Foundation Medicine teams with MD Anderson for new trial of cancer Dx

Second study to see if targeted therapy can change patient outcomes

August 15, 2014 | By   FierceDiagnostics

Foundation Medicine ($FMI) is teaming up with the MD Anderson Cancer Center in Texas for a new trial of the the Cambridge, MA-based company’s molecular diagnostic cancer test that targets therapies matched to individual patients.

The study is called IMPACT2 (Initiative for Molecular Profiling and Advanced Cancer Therapy) and is designed to build on results from the the first IMPACT study that found

  • 40% of the 1,144 patients enrolled had an identifiable genomic alteration.

The company said that

  • by matching specific gene alterations to therapies,
  • 27% of patients in the first study responded versus
  • 5% with an unmatched treatment, and
  • “progression-free survival” was longer in the matched group.

The FoundationOne molecular diagnostic test

  • combines genetic sequencing and data gathering
  • to help oncologists choose the best treatment for individual patients.

Costing $5,800 per test, FoundationOne’s technology can uncover a large number of genetic alterations for 200 cancer-related genes,

  • blending genomic sequencing, information and clinical practice.

“Based on the IMPACT1 data, a validated, comprehensive profiling approach has already been adopted by many academic and community-based oncology practices,” Vincent Miller, chief medical officer of Foundation Medicine, said in a release. “This study has the potential to yield sufficient evidence necessary to support broader adoption across most newly diagnosed metastatic tumors.”

The company got a boost last month when the New York State Department of Health approved Foundation Medicine’s two initial cancer tests: the FoundationOne test and FoundationOne Heme, which creates a genetic profile for blood cancers. Typically,

  • diagnostics companies struggle to win insurance approval for their tests
  • even after they gain a regulatory approval, leaving revenue growth relatively flat.

However, Foundation Medicine reported earlier this week its Q2 revenue reached $14.5 million compared to $5.9 million for the same period a year ago. Still,

  1. net losses continue to soar as the company ramps up
  2. its commercial and business development operation,
  • hitting $13.7 million versus a $10.1 million deficit in the second quarter of 2013.

Oncology

There has been a remarkable transformation in our understanding of

  • the molecular genetic basis of cancer and its treatment during the past decade or so.

In depth genetic and genomic analysis of cancers has revealed that

  • each cancer type can be sub-classified into many groups based on the genetic profiles and
  • this information can be used to develop new targeted therapies and treatment options for cancer patients.

This panel will explore the technologies that are facilitating our understanding of cancer, and

  • how this information is being used in novel approaches for clinical development and treatment.
Oncology _ Reprted by Dr. Aviva Lev-Ari, Founder, Leaders in Pharmaceutical Intelligence

Opening Speaker & Moderator:

Lynda Chin, M.D.
Department Chair, Department of Genomic Medicine
MD Anderson Cancer Center

  • Who pays for PM?
  • potential of Big data, analytics, Expert systems, so not each MD needs to see all cases, Profile disease to get same treatment
  • business model: IP, Discovery, sharing, ownership — yet accelerate therapy
  • security of healthcare data
  • segmentation of patient population
  • management of data and tracking innovations
  • platforms to be shared for innovations
  • study to be longitudinal,
  • How do we reconcile course of disease with PM
  • phinotyping the disease vs a Patient in wait for cure/treatment

Panelists:

Roy Herbst, M.D., Ph.D.
Ensign Professor of Medicine and Professor of Pharmacology;
Chief of Medical Oncology, Yale Cancer Center and Smilow Cancer Hospital

Development new drugs to match patient, disease and drug – finding the right patient for the right Clinical Trial

  • match patient to drugs
  • partnerships: out of 100 screened patients, 10 had the gene, 5 were able to attend the trial — without the biomarker — all 100 patients would participate for the WRONG drug for them (except the 5)
  • patients wants to participate in trials next to home NOT to have to travel — now it is in the protocol
  • Annotated Databases – clinical Trial informed consent – adaptive design of Clinical Trial vs protocol
  • even Academic MD can’t read the reports on Genomics
  • patients are treated in the community — more training to MDs
  • Five companies collaborating – comparison og 6 drugs in the same class
  • if drug exist and you have the patient — you must apply PM

Summary and Perspective:

The current changes in Biotechnology have been reviewed with an open question about the relationship of In Vitro Diagnostics to Biopharmaceuticals switching, with the potential, particularly in cancer and infectious diseases, to added value in targeted therapy by matching patients to the best potential treatment for a favorable outcome.

This reviewer does not see the movement of the major diagnostics leaders entering into the domain of direct patient care, even though there are signals in that direction.  The Roche example is perhaps the most interesting because Roche already became the elephant in the room after the introduction of Valium,  subsequently bought out Boehringer Mannheim Diagnostics to gain entry into the IVD market, and established a huge presence in Molecular Diagnostics early.  If it did anything to gain a foothold in the treatment realm, it would more likely forge a relationship with Foundation Medicine.  Abbott Laboratories more than a decade ago was overextended, and it had become the leader in IVD as a result of the specialty tests, but it fell into difficulties with quality control of its products in the high volume testing market, and acceeded to Olympus, Roche, and in the mid volume market to Beckman and Siemens.  Of course, Dupont and Kodak, pioneering companies in IVD, both left the market.

The biggest challenge in the long run is identified by the ability to eliminate many treatments that would be failures for a large number of patients. That has already met the proof of concept.  However, when you look at the size of the subgroups, we are not anywhere near a large scale endeavor.  In addition, there is a lot that has to be worked out that is not related to genomic expression by the “classic” model, but has to take into account the emrging knowledge and greater understanding of regulation of cell metabolism, not only in cancer, but also in chronic inflammatory diseases.

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WordPress.com Annual Report for 2013

The Louvre Museum has 8.5 million visitors per year. This blog was viewed about 220,000 times in 2013. If it were an exhibit at the Louvre Museum, it would take about 9 days for that many people to see it.

In 2013, there were 958 new posts, growing the total archive of this blog to 1,505 posts. There were 982 pictures uploaded, taking up a total of 253 MB. That’s about 3 pictures per day.

The busiest day of the year was September 19th with 2,501 views. The most popular post that day was Is the Warburg Effect the Cause or the Effect of Cancer: A 21st Century View?.

SOURCE

https://pharmaceuticalintelligence.com/2013/annual-report/

UPDATES on 1/4/2014

On 1/4/2014

We celebrate 1,544 articles, 5,683 tags, 303,847 views, first article 4/30/2012 – Open Access Online Scientific Journal  

UPDATED on 11/10/2013

On April 15, 2013

We celebrate 800 articles, 4040 tags, 158,147 views, first article 4/30/2012 – Open Access Online Scientific Journal

On November 10, 2013

We celebrate 1,338 articles, 5,316 tags, 275,104 views, first article 4/30/2012 – Open Access Online Scientific Journal

Encouragement by the Founder: Aviva Lev-Ari, PhD, RN

Updated CURRENT NEEDS on 1/1/2014:

We are SEEKING resources to satisfy our needs at present time:

1. Efforts to find a buyer for our Scientific Journal for 12/2014

http://pharmaceuticalintelligence.com

2. Efforts to find a Publisher for a hardcopy version of a Three Volume Series  onCardiovascular Diseases

3. Find few additional Authors for the Journal

4. Find Editors for Cardiovascular Diseases e-Books

5. Find one Editor for Infectious Diseases

6. Find one Editor for immunology

7. Find few Patent Holders in BioMed, for our Business Partner in Shanghai to be connected to Private Equity investors

8. Find Angel Investors for Venture #5

Business Portfolios

VENTURE #1:

e-Publishing: Medicine, HealthCare, Life Sciences, BioMed, Pharmaceutical

  • Open Access Online Scientific Journal

http://pharmaceuticalintelligence.com

Site statistics https://pharmaceuticalintelligence.wordpress.com/wp-admin/index.php?page=stats

  • Scoop.it!.com
  1. http://www.scoop.it/t/cardiotoxicity
  2. http://www.scoop.it/t/cardiovascular-and-vascular-imaging
  3. http://www.scoop.it/t/cardiovascular-disease-pharmaco-therapy

VENTURE #2:

1. BioMedical e-Books Series:

https://pharmaceuticalintelligence.com/biomed-e-books/

2. on Amazon’s Kindle e-Books List since 6/2013

3. Plans for Volume 1,2,3 – Hardcover

 

VENTURE #3:

International Scientific Delegations

https://pharmaceuticalintelligence.com/scientific-delegation/

  • Shanghai, May 2014 
  • Barcelona, Spain, November 2014
  • Amsterdam, May 2015
  • Geneva, November 2015

VENTURE #4:

Joint Ventures

https://pharmaceuticalintelligence.com/joint-ventures/

  • Leaders in Pharmaceutical Business Intelligence AND NEW MEDICINE, INC. [ongoing]
  • Leaders in Pharmaceutical Business Intelligence AND Bio-Tree Systems [pending Bio-Tree finding funding]
  • Leaders in Pharmaceutical Business Intelligence AND Lou Pharma [pending finding Licensees for drugs manufactured in Spain]
  • Leaders in Pharmaceutical Business Intelligence AND AlphaSzenszor Inc.
  • Leaders in Pharmaceutical Business Intelligence AND ValveCure, LLC

VENTURE #5:

Invented HERE!

1.  Development of a NEW Nitric Oxide monitor to Alpha Szenszor Inc. sensor portfolio. A concept for a low cost POC e-nose, capable of real time ppb detection of Cancer
The Cancer Team at Leaders in Pharmaceutical Business Intelligence under the leadership of Dr. Williams

2.  Development of a NEW Nitric Oxide monitor to Alpha Szenszor Inc. sensor portfolio. A concept for Inhaled Nitric Oxide for the Adult HomeCare Market –

IP by Dr. Pearlman and Dr. A. Lev-Ari

a.  iknow iNO is i-kNOw – Inhaled Nitric Oxide for the HomeCare Market

https://pharmaceuticalintelligence.com/2013/10/16/iknow-ino-is-i-know-inhaled-nitric-oxide-for-the-homecare-market/

b. electronic Book on Nitric Oxide by Nitric Oxide Team @ Leaders in Pharmaceutical Business Intelligence (LPBI)

Perspectives on Nitric Oxide in Disease Mechanisms

http://www.amazon.com/dp/B00DINFFYC

c. The rationale and use of inhaled NO in Pulmonary Artery Hypertension and Right Sided Heart Failure

Larry H. Bernstein 8/20/2012

d. Inhaled Nitric Oxide in Adults: Clinical Trials and Meta Analysis Studies – Recent Findings

3.  Cancer Genomics for NEW product development in diagnosis and treatment of Cancer Patients using sensory technology with applications for Radiation Therapy – The Cancer Team at Leaders in Pharmaceutical Business Intelligence under leadership of Dr. Sidney Kadish.

4.  Developing Mitral Valve Disease: MRI Methods and Devices for Percutaneous Mitral Valve Replacement and Mitral Valve Repair
Augmentation of Patented Technology using RF – Dr. Pearlman’s IP Non-Hardware Mitral Annuloplasty – Dr. Justin D. Pearlman

https://pharmaceuticalintelligence.com/joint-ventures/valvecure-llc/non-hardware-mitral-annuloplasty-dr-justin-d-pearlman/

5.  Novel Technology using MRI for Vascular Lesions, Tumors, Hyperactive Glands and non-Surgical Cosmetic Reconstruction – Dr. Pearlman’s IP

http://pharmaceuticalintelligence.com/biomed-e-books/series-a-e-books-on-cardiovascular-diseases/httppharmaceuticalintelligence-combiomed-e-bookscardiovascular-diseases-causes-risks-and-management/cvd-business-affairs/mitral-valve-disease-mri-methods-and-devices/

VENTURE # 6:

PRESS Coverage of Conferences

https://pharmaceuticalintelligence.com/press-coverage/

Top Authors for all days ending 2014-01-05 (Summarized)


Author Views
2012pharmaceutical 96,387
larryhbern 42,452
tildabarliya 17,394
Dr. Sudipta Saha 13,882
Dror Nir 8,909
ritusaxena 8,851
sjwilliamspa 8,456
aviralvatsa 4,681
zraviv06 2,402
anamikasarkar 2,132
Demet Sag, Ph.D., CRA, GCP 2,072
pkandala 1,818
Alan F. Kaul, PharmD., MS, MBA, FCCP 1,329
zs22 1,153
megbaker58 1,005
Aashir Awan, Phd 775
jdpmdphd 344
Ed Kislauskis 244
jukkakarjalainen 168
apreconasia 148

 

 

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Reporter: Aviva Lev-Ari, PhD, RN

Drug Discovery Chemistry

Optimizing Small Molecules for Tomorrow’s Therapeutics

April 16-18, 2013 | San Diego, CA

Conference Brochure

http://www.drugdiscoverychemistry.com/uploadedFiles/Drug_Discovery_Chemistry/13/2013-Drug-Discovery-Chemistry-Brochure.pdf

Nobel Laureate Jack Szostak to Present Plenary Keynote at Eighth Annual Drug Discovery Chemistry Conference on April 16 – Record Attendance from More than 225 Organizations and 25 Countries is Expected

Drug Discovery Chemistry is one of the few conferences for medicinal chemists working in pharma and biotech, and is focused on discovery and optimization challenges of small molecule drug candidates. New this year are Constrained Peptides and Macrocyclics and GPCR-Based Drug Design which represent areas of chemistry where evolving technologies are leading to renewed interest. They complement the most popular meetings from the past few years: Anti-Inflammatories, Fragment-Based Drug Discovery, Kinase Inhibitor Chemistry and Protein-Protein Interactions:

 – Anti-Inflammatories  [View Agenda] 4/16-17

– Fragment-Based Drug Discovery  [View Agenda] 4/16-17

– Constrained Peptides and Macrocyclics Drug Discovery  [View Agenda] 4/16-17

– Kinase Inhibitor Chemistry  [View Agenda] 4/17-18

– Protein-Protein Interactions  [View Agenda] 4/17-18

– GPCR-Based Drug Design  [View Agenda] 4/17-18

In a recent interview with Bio-IT World’s Kevin Davies, Dr. Szostak shared his thoughts on evolutionary chemistry, cyclic peptides, discovery of new small molecules for therapeutics, and his upcoming plenary keynote address: mRNA Display: From Basic Principles to Macrocycle Drug Discovery.

MEDIA GALLERY: VIDEOS

Jack Szostak Previews his Plenary Keynote for Drug Discovery Chemistry on

mRNA Display: From Basic Principles to Macrocycle Drug Discovery.

VIEW VIDEO

Jack Szostak Previews his Plenary Keynote for Drug Discovery Chemistry

In a recent interview, nobel laureate Dr. Jack Szostak shared his thoughts with Bio-IT World’s Kevin Davies on evolutionary chemistry, cyclic peptides, discovery of new small molecules for therapeutics, his upcoming plenary keynote address, and much more. On April 16, at the Eighth Annual Drug Discovery Chemistry conference, Dr. Szostak will present mRNA Display: From Basic Principles to Macrocycle Drug Discovery.


For VIDEO of Doug Treco Discusses Constrained Peptides and Macrocyclics

SCROLL DOWN THE SAME PAGE AS THE PREVIOUS VIDEO

VIEW VIDEO

Dr. Doug Treco, president & CEO of Ra Pharmaceuticals, shares recent developments in constrained peptides, macrocyclics, and how to develop peptides into a more useful class of drug. Dr. Treco will present Direct Selection of Cyclomimetics™ from mRNA Display Libraries at the Eighth Annual Drug Discovery Chemistry conference in San Diego on April 17.

List of Attendees:

Record Attendance Expected this Year! Should your Organization be on this List?
(Partial List as of 4/5)

A Star – Head – Organic Chemistry
Abbvie – Scientist – Research
Abbvie Bioresearch Ctr – Sr Scientist III – Chemistry
Abbvie Bioresearch Ctr – Sr Scientist III
AbbVie Inc – Principal Research Scientist
AbbVie Inc – Sr Scientist III – Molecular Modeling
Actelion Pharmaceuticals Ltd – Lab Head – Medicinal Chemistry
Actelion Pharmaceuticals Ltd – Sr Lab Head
Activ Motif – PostDoctoral Assoc
Addex Therapeutics – Assoc Res Dir – Structural Science
Adnexus a Bristol Myers Squibb R&D Co – Staff Scientist – Discovery
Affymax Inc – Sr Scientist II
Aileron Therapeutics Inc – Sr VP & CSO
Ajinomoto Co Ltd – Sr. Researcher
Allergan Inc – Sr Scientist – Medicinal Chemistry
Amakem NV – CoFounder & Dir External R&D – External R&D
Ambrx Inc – CTO
Amgen Inc – Principal Scientist – Pharmacokinetics & Drug Metabolism
Amgen Inc – Sr Scientist – Protein Technologies
AMRI – Dir Discovery R&D – Chemistry
AnalytiCon Discovery LLC – Exec VP Bus Dev – Natural Products
Anaspec Inc – Sr Chemist
Ardea Biosciences Inc – VP Research – Research Operations
Arena Pharmaceuticals – Research Fellow
Argenta Discovery 2009 Ltd – Sr Dir Chemistry
ARIAD Pharmaceuticals Inc – Assoc Dir Chemistry
Array BioPharma Inc – Sr Dir Cellular & Translational Biology
Asahi Kasei Pharma Co Ltd – Researcher – Lab for Medicinal Chemistry
Astellas – Scientist – Drug Discovery Research
Astellas Research Institute of American LLC – Principal Scientist – Med Chem
AstraZeneca – Assoc Principal Scientist – R&I iMed Medicinal Chemistry
AstraZeneca R&D Moelndal – Project Leader & Principal Scientist – Medicinal Chemistry & CVGI iMed
Axikin Pharmaceuticals Inc – Sr Dir Drug Dev Technologies – Drug Dev Technologies
Bayer AG – Principal Scientist
Bayer HealthCare AG – Computational Chemistry
Beijing Hanmi Pharmaceutical Co Ltd – Grp Leader Medicinal Chemistry & Analytical Chem
Ben Gurion Univ – Assoc Prof – Microbiology & Immunology & Health Sciences
Bicycle Therapeutics Ltd – CSO
Bio Rad Labs – Sales Mgr
Biogen Idec Inc – Principal Scientist – Physical Biochemistry
Biogen Idec Inc – Principal Scientist
Biogen Idec Inc – Scientist II – Medicinal Chemistry & Drug Discovery
Biogen Idec Inc – Sr Scientist & Medicinal Chemist
Biotage LLC – Specialist – Peptide Applications
Boehringer Ingelheim Pharma – Principal Scientist – Structural Research
Boehringer Ingelheim Pharma – Sr Principal Scientist – Medicinal Chemistry
Boehringer Ingelheim Pharma – Sr Scientist – Medicinal Chemistry
Boehringer Ingelheim Pharma GmbH & CO KG – Scientist – Chemical Research
BPS Bioscience Inc – Sr Research Scientist I
Brigham & Womens Hospital – Asst Prof Neurology
Bristol Myers Squibb – Grp Leader – Medicinal Chemistry
C&C Research Labs – Sr Research Scientist – Medicinal Chemistry
C&C Research Labs – Sr Researcher – CADD
Cancer Research UK Beatson Labs – Head – Chemistry
Catholic Univ of Korea – Prof – Natl Lab for Molecular Virology
Celgene – Assoc Scientist – Chemistry
Celgene – Sr Scientist – Chemistry
Celgene Avilomics Research – Sr Dir Chemistry
Celgene Corp – Sr Principal Investigator – Translational Dev
Cell Assay Innovations LLC – Founder & President
Charnwood Molecular Ltd – Head – Medicinal Chemistry
Charnwood Molecular Ltd – Mgr – Bus Dev
ChemAxon – Account Mgr
ChemAxon Ltd – Dir – Sales
ChemAxon Ltd – Principal Application Scientist
ChemBridge Corp – Exec Dir Sales & Marketing
Chemical Computing Group Inc – Principal Scientist – Scientific Support
Chinese Academy of Science – Guangzhou Institute of Biomedicine & Health
Chugai Pharmaceutical Co Ltd – Medicinal Chemist – Research
Chugai Pharmaceutical Co Ltd – Researcher
City of Hope Beckman Research Institute – Prof – Immunology
City of Hope Natl Medical Ctr – Staff Scientist – Molecular Medicine
CMD Bioscience LLC – Dir – Bus Dev
CMD Bioscience LLC – Dir Computational Chemistry
CNRS – Principal Investigator – Cancer Research
CNRS IPBS – Chemistry
Computype Inc – Market Mgr – Life Sciences
Computype Inc – Regional Sales Mgr
Cubist Pharmaceuticals Inc – Sr Scientist – Discovey Chemistry
Daiichi Sankyo Co Ltd – Assoc Sr Researcher – Discovery Research Lab
Daiichi Sankyo Co Ltd – Assoc Sr Researcher – Lead Discovery & Optimization Research Labs I
Daiichi Sankyo Co Ltd – Sr Dir – Lead Discovery & Optimization Research Labs I
Dart NeuroScience LLC – Assoc Dir – Chemistry
Dart NeuroScience LLC – Assoc Dir Chemistry
Dart NeuroScience LLC – Scientist II
Dart NeuroScience LLC – Scientist III – Leade Discovery HTS
Dart NeuroScience LLC – Scientist III
Dart NeuroScience LLC – Senior Research Assoc – Chemistry
Dart NeuroScience LLC – Sr Research Assoc – Chemistry
DEL BioPharma – Owner
DiscoveRx Corp – Dir Marketing – LeadHunter
DiscoveRx Corp – Sr Product Mgr
Dong A Pharmaceutical Co Ltd – Research Scientist
Dotmatics Ltd
E Merge Tech Global Svcs – CEO
E Merge Tech Global Svcs – Mgr – R&D
Eisai Co Ltd – Researcher – Product Creation
Eli Lilly & Co – Computational Chemist & Crystallographer
Eli Lilly & Co – Endocrine
Eli Lilly & Co – Sr Advisor – DCR&T
Eli Lilly & Co – Sr Research Advisor – Discovery Chemistry
Eli Lilly & Co – Sr Research Advisor – Discovery Chemistry Research
Eli Lilly & Co – Sr Research Scientist – Discovery Chemistry
EMD Serono Research & Development Institute Inc – Chemistry
EMD Serono Research & Development Institute Inc – Head – Drug Target Innovation & External Innovations
EMD Serono Research & Development Institute Inc – Sr Scientist – Chemistry
EMD Serono Research & Development Institute Inc – Sr Scientist – Medicinal Chemistry
Emory Univ – Post Doc Fellow
Ensemble Therapeutics – CSO
Entelos Inc – Dir Marketing
ESBS – Research Dir Receptord & Membrane Proteins – CNRS Biotechnology
ETH Zurich – Sr Scientist – Pharmaceutical Sciences
Evotec Inc – Project Leader – Discovery
Ewha Womans University – Prof
F Hoffmann La Roche Inc – Consultant – Medical Affairs
F Hoffmann La Roche Inc – Sr Research Leader – PR&D Discovery Chemistry
F Hoffmann La Roche Inc – VP & Global Head of Discovery Technologies – pRED & Discovery Technologies
Ferring Research Institute – Sr Scientist – Medicinal Chemistry
FLAMMA – Dir – Bus Dev
Full Spectrum Genetics Inc – Head – Bioinformatics
GE Healthcare – Product Specialist
Genentech Inc – Assoc Dir Structural Biology
Genentech Inc – Postdoc Research Fellow – Structural Biology
Genentech Inc – Scientist – Medicinal Chemistry
Genentech Inc – Scientist – Protein Engineering
Genentech Inc – Scientist & Team Leader – Medicinal Chemistry
Genentech Inc – Sr Mgr – Bus Dev
Genomics Institute of the Novartis Research Foundation – Principal Investigator – Structural Biology
Gilead Sciences Inc – Dir Biology
Gilead Sciences Inc – Dir Medicinal Chemistry
Gilead Sciences Inc – Research Scientist II
GL Chemtech Intl Ltd – Dir Bus Dev
Gwangju Institute of Science & Technology – Prof – Life Sciences
Harvard Medical School – Hematology Oncology
Hauptman Woodward Institute – Sr Research Scientist – Structural Biology
Helmholtz Zentrum Muenchen GmbH – Head – Assy Dev & Sxcreening Platform
Helsinn Therapeutics Inc – Sr Assoc – Tech Affairs
Heptares Therapeutics Ltd – Head – Biomolecular Structure
Hewlett Packard Oregon
Imgenex Corp – Principal Consultant – Corp Dev
Imgenex Corp – Product Mgr – Marketing
In Silico Biosciences – CSO – Computational Neuropharmacology
Indiana University – Research Asst Prof – Biochemistry & Molecular Biology
Industry Canada – Sr Patent Examiner – Organic 02
INSERM – Principal Investigator – CRCM CNRS
INSERM – Prof
Integral BioSciences – Research Scientist – Med Chem
Iowa State University – Principal Investigator – Biomedical Sciences
Ironwood Pharmaceuticals Inc – MedChem
Janssen Pharmaceuticals Inc – Sr Scientist – Scale Up Synthesis
Japan Tobacco Inc – Research Scientist – Central Pharmaceutical Research Lab
Japan Tobacco Inc – Researcher
Japan Tobacco Inc – Sr Dir Project & Portfolio Mgmt – Project & Portfolio Mgmt
Johns Hopkins University – Prof – Biology
Johnson & Johnson Pharmaceutical R&D – Assoc Scientist – Chemistry
Johnson & Johnson Pharmaceutical R&D – Chemist – Med Chem
Johnson & Johnson Pharmaceutical R&D – Physiological Systems
Johnson & Johnson Pharmaceutical R&D – Principal Scientist – Immunology Chemistry
Johnson & Johnson Pharmaceutical R&D – Sr Scientist – Chemistry
JT Central Pharmaceutical Research Institute – Research Scientist – Chemistry
Jubilant Discovery
Kalexsyn Inc
King Saud University – Pharmaceutical Chemistry
Korea Research Institute of Chemical Technology – Principal Researcher Drug Discovery Research
Lexicon Pharmaceuticals – Assoc Dir – Chem Tech
Life Chemicals Inc – Mgr – Bus Dev & Sales
Life Chemicals Inc – VP Marketing & Sales
LipoScience – CSO
Los Alamos Natl Lab – PostDoc Research Assoc – Bioscience
Lundbeck Research USA – Principal Scientist – Discovery Chemistry & DMPK
Massachusetts General Hospital – Prof – Genetics
Mayo Clinic – Asst Prof – Immunology
Medivation Inc – Dir Medicinal Chemistry
Merck – Principal Scientist
Merck Serono Research – Sr Dir Lead Discovery Technologies – MS DTC Strategic Operations Global Tech
Mitsubishi Tanabe Pharma Corp – Research Scientist – Medicinal Chemistry
MorphoSys AG – Sr Scientist
Natl Institute of Biological Science – Sr Investigator
Natl Taiwan University – Research Assoc – Chemisty
Natl Univ of Singapore – Assoc Prof – Chemistry
NIH CIT – CIO & Dir
NIH NCATS – Research Scientist – Probe Dev Ctr
NIH NINDS – Investigator – Basic Neuroscience
Novartis Institute for Tropical Diseases Pte Ltd – Investigator III – Chemistry
Novartis Institutes for BioMedical Research Inc – Dir Bus Dev
Novartis Institutes for BioMedical Research Inc – Presidential Postdoctoral Fellow
Novartis Pharma AG – Investigator III – Global Discovery Chemistry
Novartis Pharma AG – Proteomic Chemistry
Novartis Pharma AG – Research Investigator – NIBR
Nuevolution AS – Research Scientist
Nuevolution AS – Sr Scientist – Molecular Design
Oncodesign SA – CSO
Onyx Scientific Ltd – Dir Bus Dev
OpenEye Scientific Software Inc – Dir Emerging Markets – Emerging Markets
OpenEye Scientific Software Inc – Sr Applications Scientist
Ora Inc – Dir Pre Clinical Svcs
Original Biomedical Corp – Bus Dev
Peptron Inc – CEO
Pfizer Animal Health – Sr Principal Scientist
Pfizer Global R&D Groton Labs – Sr Principal Scientist – Structure Biology & Biophysics
Pfizer Inc – Assoc Dir – Prizer Animal Health
Pfizer Inc – Assoc Research Scientist – Chemical Sciences
Pfizer Inc – VP Chemistry
Pfizer Research Labs – Principal Scientist – Worldwide Medicinal Chemistry
PharmaCore Inc – Dir Bus Dev
PharmaCore Inc – President
Pharmacyclics Inc – Research Scientist III – Medicinal Chemistry
Polish Academy Of Sciences – Institute of Organic Chemistry
Polyphor Ltd – CSO & CoFounder
POSTECH – Assoc Prof
Prestwick Chemical – Head – Medicinal Chemistry
Prestwick Chemical – VP US Operations
Principia BioPharma Inc – Assoc Dir
Protagonist Therapeutics Inc – President & CEO
Purdue University – Assoc Prof – Medicinal Chemistry & Molecular Pharmacology
Quantum Tessera Consulting LLC – President and CSO
RA Pharmaceuticals Inc – President & CEO
RA Pharmaceuticals Inc – Scientist II
Receptos Inc – Assoc Dir – Biology
Receptos Inc – Dir Structural Biology
Receptos Inc – Scientist I
Roche Diagnostics GmbH – Dir Bio Analysis – Antibody Dev
Roche NimbleGen Inc – Sr Scientist
Rockefeller University – Richard M & Isabel P Furlaud Prof – Molecular Biology & Biochemistry
Rutgers University – Asst Research Prof – CABM
Sanofi Aventis – Head – In Silico Drug Discovery
sanofi aventis Grp – Project Leader
Santen Pharmaceutical – Researcher – Synthetic Chemistry Group
Schrodinger Inc – Applications Scientist
Science for Solutions LLC – President
Scripps Research Institute – Asst Prof – Molecular Biology
Scripps Research Institute – PostDoc Assoc – Molecular Therapeutics
Scripps Research Institute – Prof – Chemical Physiology
Scripps Research Institute – Research Assoc – Chemistry
Scripps Research Institute – Visiting Scientist – Chemical Physiology
Selcia Ltd – Grp Leader – Biology
Senomyx Inc – Principal Scientist – Chemistry
SENSIQ – COO
SENSIQ – CSO – Bioinstrumentation
SENSIQ – VP Marketing – Sales & Marketing
Shionogi & Co Ltd
SIGA Technologies Inc – CSO
Simulations Plus Inc – Research Fellow – Life Sciences
Simulations Plus Inc – Team Leader – Cheminformatics Study
Sookmyung Womens University – Student – College of Pharmacy
SRI Intl – Program Dir Medicinal Chemistry
St Jude Childrens Research Hospital – Post Doc Fellow – Chemical Biology & Therapeutics
St Jude Childrens Research Hospital – Postdoc – Chem Bio & Therapeutics
St Jude Childrens Research Hospital – Research Asst – Chemical Biology & Therapeutics
St Petersburg State Institute of Technology – Lab of Molecular Pharmacology
Stanford University – Assoc Prof – Bioengineering
Stanford University – Graduate Student – Kobilka Lab
Stanford University – Research Assoc – Chemical & Systems Biology
Structural Genomics Consortium – Postdoc Research Assoc – Epigenetics Probes Team
Sygene Intl Ltd – Sr Lead Investigator – Medchem
Sygnature Discovery Ltd – CEO
Sygnature Discovery Ltd – Dir New Bus Dev
SYNthesis Shanghai – Managing Dir
Synthonix – Bus Dev Mgr
Synthonix – CoFounder & President & CEO
Taiho Pharmaceutical Co Ltd – Sr Scientist – Medicinal Chemistry
Takeda California – Assoc Scientist
Takeda California – Scientist – Discovery Biology
Takeda California – Sr Scientist – Chemistry
Takeda California – Sr Scientist – SB & Ab Core Science & Technology
Takeda Pharmaceutical Co Ltd – Principal Scientist – Structural Biology
Takeda Pharmaceutical Co Ltd – Researcher – Medicinal Chemistry Lab
Takeda Pharmaceutical Co Ltd – Researcher – Pharmaceutical Research
Takeda San Diego – Dir Immunology Chemistry
Takeda San Diego – Scientist II
TC Scientific Inc – CEO
Theravance Inc – Research Assoc – Medicinal Chemistry
Theravance Inc – Scientist – Med Chem
Theravance Inc – Sr Research Advisor – Medicinal Chemistry
Theravance Inc – VP Molecular & Cellular Biology
Thermo Fisher Scientific Inc – Bus Mgr
Topharman USA
Tranzyme Pharma Inc – Sr VP Research & Preclinical Dev
Tranzyme Pharma Inc – VP IP & Operations
Tsinghua Univ – Medicinal Chemistry
UCB Pharma – Principal Scientist – CADD
UCB Pharma – Computational Medicinal Chemist
University of California Los Angeles – Prof – Molecular Imaging
University of California San Diego – Asst Prof – Chemistry & Biochemistry
University of California San Diego – Postdoc – Chemistry & Biochemistry
University of California San Diego – Prof – Clinical Medicine & Rheumatology
University of California San Diego – Prof – Molecular Biology
University of California San Francisco – Assoc Adjunct Prof – Lab Medicine
University of Central Florida – GRA – Chemistry
University of Cincinnati – Assoc Prof – Environmental Health
University of Essex – Prof – Computational Chemistry
University of Illinois Chicago – Prof – Biopharmaceutical Sciences
University of Maryland Baltimore – Grollman Glick Prof – Pharmaceutical Sciences
University of Miami – Dir Drug Discovery – Diabetes Research Institute
University of Navarra – Dir – Small Molecule Discovery
University of New South Wales – Postgraduate Student – Chemistry
University of Paris Diderot – Sr Research Assoc – Inserm UMR S973
University of Pittsburgh – Prof & Chair – Microbiology & Molecular Genetics
University of Pittsburgh – Research Asst Prof – Computational & Systems Biology
University of Southern California – Assoc Prof – Pharmacology & Pharmaceutical Sciences
University of Southern California – Scientist – Molecular & Computational Biology
University of Southern California – Molecular Microbiology & Immunology
University of Texas Dallas – Assoc Prof – Psychiatry & Neurology & Neurotherapeutics
University of Texas Houston – Asst Prof – Stem Cell Research
University of Toronto – Principal Investigator – Medical Biophysics
University of Utah – Research Assoc
University of Warsaw – Institute of Genetics and Biotechnology
University of York – Prof – Chemistry
University of Zurich – Scientist – Biochemistry
University Pompeu Fabra – Research Assoc – Medicinal Chemistry
Vanderbilt University – Research Fellow – Ctr for Neuroscience Drug Discovery
Vertex Pharmaceuticals Inc – Med Chem
Vertex Pharmaceuticals Inc – Research Fellow II – Biology
Vertex Pharmaceuticals Inc – Research Scientist – Chemistry
Vertex Pharmaceuticals Inc – Research Scientist I – Biology
Vidya Bharati College – Asst Prof – Chemistry
Vrije University Brussels – Exec Dir & Prof – Mol & Cellular Interactions
Vrije University Brussels – Prof Research Grp of Organic Chemistry – Bioengineering Sciences & Chemistry
Wayne State University – Research Scientist – Pathology & Oncology
Wichita State University – WSU Foundation Distinguished Prof – Chemistry
Wistar Institute – Staff Scientist
WuXi AppTec – Dir Bus Dev – Chemistry Svcs
X Chem Pharmaceuticals Inc – Dir Chemistry
X Chem Pharmaceuticals Inc – Sr Dir Lead Discovery
Yale University – Assoc Prof – Lab Medicine & Pharmacology
Yonsei University – Prof – Biochemistry
Yonsei University – Prof – Biotechnology

 

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