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37th Annual J.P. Morgan HEALTHCARE CONFERENCE: #JPM2019 for Jan. 8, 2019; Opening Videos, Novartis expands Cell Therapies, January 7 – 10, 2019, Westin St. Francis Hotel | San Francisco, California, Volume 2 (Volume Two: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS and BioInformatics, Simulations and the Genome Ontology), Part 1: Next Generation Sequencing (NGS)
37th Annual J.P. Morgan HEALTHCARE CONFERENCE: #JPM2019 for Jan. 8, 2019; Opening Videos, Novartis expands Cell Therapies, January 7 – 10, 2019, Westin St. Francis Hotel | San Francisco, California
Reporter: Stephen J. Williams, PhD
The annual J.P. Morgan Healthcare Conference is the largest and most informative healthcare investment symposium in the industry, bringing together industry leaders, emerging fast-growth companies, innovative technology creators, and members of the investment community.
Joe Biden on the Fight Against Cancer
Former Vice President of the United States joined the J.P. Morgan Healthcare Conference to discuss cancer initiatives.
Novartis Talks Move to Cell and Gene Therapies at JPM
Published: Jan 08, 2019By Alex Keown from Biospace.com
Denis Linine / Shutterstock
Following a strong post-hoc analysis of mid-stage data in the fall of 2018, Novartis announced this morning the company’s experimental humanized anti-P-selectin monoclonal antibody was crizanlizumab granted Breakthrough Therapy Status by the U.S.Food and Drug Administration (FDA).
Crizanlizumab received the designation as a treatment for the prevention of vaso-occlusive crises (VOCs) in patients of all genotypes with sickle cell disease (SCD). VOCs, which can be extremely painful for patients, happen when multiple blood cells stick to each other and to blood vessels, causing blockages.
The designation was awarded following results from the Phase II SUSTAIN trial, which showed that crizanlizumab reduced the median annual rate of VOCs leading to health care visits by 45.3 percent compared to placebo. The SUSTAIN study also showed that crizanlizumab significantly increased the percentage of patients who did not experience any VOCs vs placebo, 35.8 percent vs. 16.9 percent.
The FDA designation came one day after the Swiss pharma giant laid out its map for a future of success, sustainability and, if things work out, respect from consumers. In an interview with CNBC Monday, Novartis Chief Executive Officer Vas Narasimhan noted that the company is looking to become an entity that doesn’t draw its profits from treating disease, but will make money by providing cures. He pointed to the moves Novartis has made toward gene and cellular therapies that have the potential to cure patients of various diseases in what many researchers hope could be a “one-and-done” treatment. Narasimhan told CNBC that cures are what society wants and that is something they will value. The challenge will be determining the payment system.
As an example, the company is eying potential approval of a gene therapy for spinal muscular atrophy (SMA), a fatal genetic disease marked by progressive, debilitating muscle weakness in infants and toddlers. Novartis’ gene therapy Zolgensma is expected to be approved by the FDA this year and could have a price tag of between $4 and $5 million. While significantly high, non-profit SMA groups have already suggested that the gene therapy treatment could be more cost-effective than Spinraza, the only approved SMA treatment on the market.
During its presentation at J.P. Morgan, Novartis pointed to the moves it has made as the company pivots to this future of gene and cell therapies. The presentation noted that over the course of 2018, the company made several deals to sell off non-essential businesses, such as the $13 billion sale of its share of a consumer health business to partner GlaxoSmithKline. Not only that, but Novartis also made significant acquisitions to reshape its portfolio, including the $8.7 billion acquisition of AveXis for the SMA gene therapy. The deal for AveXis wasn’t the only gene therapy deal the company struck. Novartis began 2018 with a deal for Spark Therapeutics’ gene therapy Luxturna, a one-time gene therapy to restore functional vision in children and adult patients with biallelic mutations of the RPE65 (retinal pigment epithelial 65 kDa protein) gene.
In his interview with CNBC, Narasimhan said the company is about “platforms,” which also includes radio-ligand therapy. The company forged ahead in that area with two acquisitions, Advanced Accelerator Applications and Endocyte. Radiopharmaceuticals like Endocyte’s Lu-PSMA-617 are innovative medicinal formulations containing radioisotopes used clinically for both diagnosis and therapy. When the Endocyte deal was announced, Novartis noted the field is expected to become an increasingly important treatment option for patients, as well as a key growth driver for the company’s oncology business.
Other posts on the JP Morgan 2019 Healthcare Conference on this Open Access Journal include:
Leaders in the CAR-T Field Are Proceeding With Cautious Hope
Reporter: Stephen J. Williams, Ph.D.
It wasn’t a long time ago, in fact the May 26, 2014 Cover Story in Forbes entitled “Is This How We’ll Cure Cancer” with cover photo of Novartis CEO Joseph Jimenez and subtitle “Will This man Cure Cancer?” highlighted the promise of CAR-T therapy as the ‘magic bullet’ therapy which will eventually cure all cancer. However, over the years, the pioneers of such therapy, while offering impressive clinical results, caution not to get to eager in calling CAR-T as the end-all-be-all cure but insist there are many issues that need be resolved.
The Allogenic Approach
In an interview for LabBiotech.eu Phillip Hemme had a discussion (and wonderful writeup) with André Choulika, the CEO of the French CAR-T miracle Cellectis on the current state of CAR-T therapy for cancer. Below is the interview in full as ther ae multiple important point Dr. Choulika mentioned, including how much is needed to be done in the field.
CAR-T is solidifying in everybody’s mind as the next revolution in Cancer treatment. But there is still a lot to do…That’s basically what came out from my discussion with André Choulika, the CEO of the French CAR-T miracle Cellectis.
Cellectis is probably the most successful Biotech in France. It was founded in 1999 by Choulika himself (not alone though), following the discovery of meganucleases ability to change gene editing. Today, Cellectis is a well-known Biotech company counting over 100 employees end of October and having a market cap north of 1 Billion euros.
The company is now focused on the development of allogenic CAR-T (from generic donors – i.e. not from the patient themself). With these universal CAR-T candidates (UCARTs). Cellectis has signed a massive partnership with the French pharma Servier, as well as Pfizer (which owns 8% of Cellectis), and has just announced two big milestones for the company within the last few weeks.
Let’s start directly with the latest news…People seemed over-enthusiastic about UCART19…even the New York Times wrote about it. What do you think?
It’s a great news for Cellectis even though it’s still a very early result, in a single patient only. What’s important for us is that the first human patient received our treatment without showing any adverse effects (such as no cytokinetic storm) and our CAR-T cells were still active in the body 3 months after the injections.
Now, we have to expand the clinical trials to several patients and showing data from a cohort of patients. We are now on track to file the clinical trial application by the end of the year.
Your approach in the CAR-T is pretty unique. You are using donor’s cells to treat many different patients, whereas most CAR-T approaches are autologous (i.e. engineered the patient’s own cells). Is the future in CAR-T the allogenic approach alone?
When we started to move into the CAR-T field we were pretty reluctant because there are not many examples of commercial success in the field yet. But CAR-T has still attracted many big players such as Novartis, Celgene, Juno or Kite. These each have a strong involvement in making autologous therapies work commercially (Celgene especially, which makes most of its revenue from groundbreaking and pricey cancer drugs).
On our side, we want to make this therapy accessible to a larger population and have good market access at the end. We have already pretty good reason to think it could work out well for us. We’ll see though…
Comment:Reuters published a report a few weeks ago estimating the cost of autologous CAR-T could be above $450K per treatment, which would make it economically not realistic for the healthcare payers.
CAR-T seems to be extremely hype right now. At BIO-Europe 2015, I had the impression everybody was talking about CAR-T. Do you think it could have the same impact as monoclonal antibodies?
What’s interesting with CAR-T is that you can target cells which expresses less receptors (10k receptors instead of 100k for monoclonal antibodies). This increases the targets for CAR-T and the possibilities linked.
But there are also downsides. Tissues with low expressions can become targets too and CAR-T cells would start attacking healthy cells.
People should not overemphasise CAR-T. We are still at the beginning of the beginning of this technology. And it will probably have to be combined with surgery or checkpoint inhibitors.
You seem pessimistic about CAR-T…?
I am just trying to be more realistic, even though I am super positive about the technology. It will bring something really great to Haematology field, but is not a cure for Cancer. It’s more of a long-haul race in the right direction as opposed to fast results, and we expect great things perhaps 20 years down the line as opposed to 2016.
But yes, it will probably not be the miracle product some people are talking about.
As for every early technology, there are many challenges associated with its development. What are the main ones worth discussing?
I would say you have four main challenges…
The administration of the cells will be challenging. We have to find way of injecting repeated doses of the product (to ensure the therapy is fully effective seeing as CAR-T cells have a limited lifespan). This is difficult because of immunogenicty against the therapy.
Secondly, combination will play an essential role too and checkpoint inhibitors should be involved.
The last two are linked to the targets.
As I mentioned before, CAR-T can be too sensitive and one way to control that would be to induce “logic gates” where the cells would only act if a combination of receptors would be present. The last challenge is to find other antigens.
Most of the CAR-T cells today target the same antigen: CD19+. We should find new antigens and many companies are on the track, including us.
An anti-CD19 CAR-expressing T cell recognizing a CD19+ (Source: Kochenderfer et al., Nature Reviews Clinical Oncology 10, 267-276, doi: 10.1038/nrclinonc.2013.46)
Autologous CART therapy
Dr. Carl June of University of Pennsylvania, who has helped pioneer the field of CAR-T therapy for leukemia, has also been cautiously hopeful on the progress of the therapy. In his 2015 AACR National Meeting address, he highlighted some achievements they had with CAR-T therapy in both hematologic as well as solid tumors however it was stressed that there is much work to do with regards to optimization of the system, characterization of new tumor antigens for diverse tumor types, as well as the need to develop optimal treatment strategies to mitigate toxicities. Indeed many of the pioneers in the field have been proactive in helping to develop pharmacovigilance, safety, and regulatory strategies (highlighted in a post found here: NIH Considers Guidelines for CAR-T therapy: Report from Recombinant DNA Advisory Committee and mitigating toxicities in a post Steroids, Inflammation, and CAR-T Therapy) and much credit should be given to these researchers.
Cancer Research Institute’s Breakthroughs in Cancer Immunotherapy Webinar Series are offered free to the public and feature informative updates from leaders in cancer immunotherapy, followed by a moderated Q&A. On June 10, 2013, Carl H. June, M.D., a specialist in T cell biology and lymphocyte activation at the Perelman School of Medicine, University of Pennsylvania, discussed his groundbreaking work that has led to remarkable remissions of advanced cancer. He focused on recent and ongoing successes in developing treatments with T cells that have been genetically engineered to target cancer. Called chimeric antigen receptor T cells (CAR T cells), these modified immune cells have proven effective at eliminating cancer in some patients, and offer great hope for this emerging strategy in cancer immunotherapy. For more information on this webinar, or to register for upcoming webinars, please visit www.cancerresearch.org/webinars.
Below are reports from the 2015 American Society of Hematology Conference by Novartis on results from CTL109 CART therapy trials. One trial is on response rate in B-cell lymphomas and follicular cell lymphomas while the second report is ongoing trial results in childhood refractory ALL, both conducted at University of Pennsylvania.
Novartis announced Sunday data from an ongoing Phase IIa study demonstrating that the experimental chimaeric antigen receptor T-cell (CART) therapy CTL019 led to an overall response rate (ORR) at three months of 47 percent in adults with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and an ORR of 73 percent in adults with follicular lymphoma. The results of the trial were presented at the American Society of Hematology annual meeting.
Findings from the study, which was conducted by the University of Pennsylvania’s Perelman School of Medicine, include 15 adults with DLBCL and 11 with follicular lymphoma who were evaluable for response. Results showed that three patients with DLBCL who achieved a partial response (PR) to treatment at three months converted to complete response (CR) by six months. In addition, three patients with follicular lymphoma who achieved a PR at three months converted to CR by six months.
Novartis added that one DLBCL patient with a PR at three months experienced disease progression at six months after treatment. Further, one follicular lymphoma patient with a PR at three months who remained in PR at nine months experienced disease progression at approximately 12 months after treatment. The company indicated that median progression-free survival was 11.9 months for patients with follicular lymphoma and 3 months for those with DLBCL.
In the study, four patients developed cytokine release syndrome (CRS) of grade 3 or higher. Novartis noted that during CRS, patients typically experience varying degrees of influenza-like symptoms with high fevers, nausea, muscle pain, and in some cases, low blood pressure and breathing difficulties. Meanwhile, neurologic toxicity occurred in two patients in the trial, including one grade three episode of delirium and one possibly related grade five encephalopathy.
“These data add to the growing body of clinical evidence on CTL019 and illustrate its potential benefit in the treatment of relapsed and refractory non-Hodgkin lymphoma,” commented lead investigator Stephen Schuster. Novartis indicated that the findings keep CTL019 on track for submission to the FDA in 2017. Usman Azam, global head of Novartis’ cell and gene therapies unit, said “we remain consistent again with the data set.”
“It’s an attractive population, it’s a population that continues to have a huge unmet need, it’s a cornerstone of our investments,” Azam remarked. Analysts expect CART therapies, once approved, to cost up to $450 000 per patient. Novartis acknowledged that prices will be high, but declined to give further details. “With any disruptive innovation that comes, initially, cost of goods is very challenging,” Azam said, adding “as time goes on, and more patients are treated, we will simplify that cost base.”
Novartis AG (NVS)’s Experimental Therapy Wipes Out Blood Cancer in 93 Percent of Patients
Reported in Biospace.com (for full article see here)
Novaritis and University of Pennsylvania reported results of the CTL019 CART trials for the treatment of children with relapsed/refractory acute lymphoblastic leukemia at the 2015 Annual Hemotologic Society Meeting. 55 of 59 patients, or 93 percent, experienced complete remissions with CTL019. The study did show that at the end of one year, 55 percent of patients had a remission-free survival rate and that 18 patients continued to show complete remission following one year
Other posts on the Open Access Journal on CAR-T therapy include
Liver Toxicity halts Clinical Trial of IAP Antagonist for Advanced Solid Tumors
Curator: Stephen J. Williams, Ph.D.
UPDATED 8/12/2022
Athough not related to IAP Antagonists this update does report 2 deaths from IDILI or idiosynchratic drug induced liver injury from a gene therapy trial using an AAV (adeno associated virus) targeting the disease spinal muscular atrophy. Please see below after reading about IDILI.
A recent press release on FierceBiotech reported the FDA had put a halt on a phase 1 study for advanced refractory solid tumors and lymphomas of Curis Inc. oral inhibitor of apoptosis (IAP) antagonist CUDC-427. The FDA placed the trial on partial clinical hold following reports of a death of a patient from severe liver failure. The single-agent, dose escalation Phase 1 study was designed to determine the maximum tolerated dose and recommended doses for a Phase 2 trial. The press release can be found at:
According to the report one patient with breast cancer that had metastasized to liver, lungs, bone, and ovaries developed severe hepatotoxicity as evidenced by elevated serum transaminase activities (AST and ALT) and hyper-billirubinemia. Serum liver enzyme activities did not attenuate upon discontinuation of CUDC-427. This was unlike prior experience to the CUDC-427 drug, in which decreased hepatic function was reversed upon drug discontinuation. The patient died from liver failure one month after discontinuation of CUDC-427.
It was noted that no other patient had experienced such a serious, irreversible liver dysfunction.
Although any incidence of hepatotoxicity can be cause for concern, the incidence of IDIOSYNCRATICIRREVERSIBLE HEPATOTOXICITY warrants a higher scrutiny.
Four general concepts can explain toxicity profiles and divergences between individuals:
Toxicogenomics: Small differences in the genetic makeup between individuals (such as polymorphisms (SNP) could result in differences in toxicity profile for a drug. This ais a serious possibility as only one patient presented with such irreversible liver damage
Toxicodynamics: The toxicologic effect is an extension of the pharmacologic mechanism of action (or lack thereof: could there have been alternate signaling pathways activated in this patient or noncanonical mechanism)
Toxicokinetic: The differences in toxicological response due to differences in absorption, distribution, metabolism, excretion etc. (kinetic parameters)
Idiosyncratic: etiology is unknown; usually a minority of adverse effects
Since there is not enough information to investigate toxicogenomic or toxicokinetic mechanisms for this compound, the rest of this post will investigate the possible mechanisms of hepatotoxicity due to IAP antagonists and clues from other clinical trials which might shed light on a mechanism of toxicity (toxicodynamic) or idiosyncratic events.
Therefore this post curates the current understanding of drug-induced liver injury (DILI), especially focusing on a type of liver injury referred to as idiosyncratic drug-induced liver injury (IDILI) in the context of:
Targeted and newer chemotherapies such as IAP antagonists
Current concepts of mechanisms of IDILI including:
i) Inflammatory responses provoked by presence of disease
ii) Cellular stresses, provoked by disease, uncovering NONCANONICAL toxicity pathways
iii) Pharmacogenomics risk factors of IDILI
Eventually this post aims to stimulate the discussion:
Given inflammation, genetic risk factors, and cellular stresses (seen in clinical setting) have been implicated in idiosyncratic drug-induced liver injury from targeted therapies, should preclinical hepatotoxicity studies also be conducted in the presence of the metastatic disease?
Does inflammation and cellular stress from clinical disease unmask NONCANONICAL pharmacologic and/or toxicological mechanisms of action?
Classification of types of Cellular Liver injury: A listing of types of cellular injury is given for review
I. Hepatic damage after Acute Exposure
A. Cytotoxic (Necrotic): irreversible cell death characterized by loss of cell membrane integrity, intracellular swelling, nuclear shrinkage (pyknosis) and eventual cytoplasmic breakdown of nuclear DNA (either by a process known as karyolysis or karyorhexus) localized inflammation as a result of release of cellular constituents. Intracellular ATP levels are commonly seen in necrotic death. Necrosis, unlike apoptosis, does not require a source of ATP. A nice review by Yoshihide Tsujimoto describing and showing (by microscopy) the differences between apoptosis and necrosis can be found here.
B. Cholestatic: hepatobiliary dysfunction with bile stasis and accumulation of bile salts. Cholestatic injury can result in lipid (particularly cholesterol) accumulation in cannicular membranes resulting in decreased permeability of the membrane, hyperbillirubinemia and is generally thought to result in metabolic defects.
C. Lipid Peroxidation: free radical generation producing peroxide of cellular lipids, generally resulting in a cytotoxic cell death
II. Hepatic damage after Chronic Exposure
A. Chirrotic: Chronic morphologic alteration of the liver characterized by the presence of septae of collagen distributed throughout the major portion of the liver; Forms fibrous sheaths altering hepatic blood flow, resulting in a necrotic process with scar tissue; Alteration of hepatic metabolic systems.
B.Carcinogenesis
III. Idiosyncratic Drug Induced Liver Injury
The aforementioned mechanisms of hepatotoxicity are commonly referred to as the “intrinsic” (or end target-organ) toxicity mechanisms. Idiosyncratic drug-induced liver injury (IDILI) is not well understood but can be separated into allergic and nonallergic reactions. Although the risk of acute liver failure associated with idiosyncratic hepatotoxins is low (about 1 in ten thousand patients) there are more than 1,000 drugs and herbal products associated with this type of toxic reaction. Idiosyncratic drug induced liver failure usually gets a black box warning from the FDA. Idiosyncratic drug-induced liver injury differs from “intrinsic” toxicity in that IDILI:
Happens in a minority of patients (susceptible patients)
Not related to drug’s pharmacologic mechanism of action (trovafloxacin IDILI vs. levofloxacin)
A great review in Perspectives in Pharmacology written by Robert Roth and Patricia Ganey at Michigan State University explains these differences between intrinsic and idiosyncratic drug-induced hepatotoxicity[1] (however authors do note that there are many similarities between the two mechanisms). It is felt that drug sensitivity (allergic) and inflammatory responses (nonallergic) may contribute to the occurrence of IDILI. For instance lipopolysaccharide (LPS) form bacteria can potentiate acetaminophen toxicity. In fact animal models of IDILI have been somewhat successful:
co-treatment of rats and mice with nontoxic doses of trovafloxacin (casues IDILI in humans) and LPS resulted in marked hepatotoxicity while no hepatotoxicity seen with levofloxacin plus LPS[2]
correlates well with incidence of human IDILI (adapted from a review Inflammatory Stress and Idiosyncratic Hepatotoxicity: Hints from Animal Models (in Pharmacology Reviews)[3]. Idiosyncratic injury damage has been reported for diclofenac, halothane, and sulinac. These drugs also show hepatotoxicity in the LPS model for IDILI.
Roth and Ganey suggest the reason why idiosyncratic hepatotoxicity is not seen in most acute animal toxicity studies is that, in absence of stress/inflammation IDILI occurrence is masked by lethality but stress/inflammation shifts increases sensitivity to liver injury at a point before lethality is seen
Figure. Idiosyncratic toxic responses of the liver. In the absence of stress and/or genetic factors, drug exposure may result in an idiosyncratic liver injury (IDILI) at a point (or dose) beyond the therapeutic range and lethal exposure for that drug. Preclinical studies, usually conducted at sublethal doses, would not detect DILI . Stress and/or genetic factors sensitize the liver to toxic effects of the drug (synergism) and DILI is detected at exposure levels closer to therapeutic range. Note IDILI is not necessarily dose-dependent but cellular stress (like ROS or inflammation) may expose NONCANONICAL mechanisms of drug action or toxicity which result in IDILI. Model adapted from Roth and Ganey.
What Stress factors contribute to IDILI?
Various stresses including inflammation from bacterial, viral infections ,inflammatory cytokines and stress from reactive oxygen (ROS) have been suggested as mechanisms for IDILI.
Inflammation/Cytokines (also discussed in other sections of this post): Inflammation has long been associated with human cases of DILI. Many cytokines and inflammatory mediators have been implicated including TNFα, IL7, TGFβ, and IFNϒ (viral infection) leading some to conclude that serum measurement of cytokines could be a potential biomarker for DILI[4]. In addition, ROS (see below) is generated from inflammation and also considered a risk factor for DILI[5].
Reactive Oxygen (ROS)/Reactive Metabolites: Oxidative stress, either generated from reactive drug metabolites or from mitochondrial sources, has been shown to be involved in apoptotic and necrotic cell death. Both alterations in the enzymes involved in the generation of and protection from ROS have been implicated in increased risk to DILI including (as discussed further) alterations in mitochondrial superoxide dismutase 2 (SOD2) and glutathione S-transferases. Both ROS and inflammatory cytokines can promote JNK signaling, which has been implicated in DILI[6].
Dr. Neil Kaplowitz suggested that we:
“develop a unifying hypothesis that involves underlying genetic or acquired mitochondrial abnormalities as a major determinant of susceptibility for a number of drugs that target mitochondria and cause DILI. The mitochondrial hypothesis, implying gradually accumulating and initially silent mitochondrial injury in heteroplasmic cells which reaches a critical threshold and abruptly triggers liver injury, is consistent with the findings that typically idiosyncratic DILI is delayed (by weeks or months), that increasing age and female gender are risk factors and that these drugs are targeted to the liver and clearly exhibit a mitochondrial hazard in vitro and in vivo. New animal models (e.g., the Sod2(+/-) mouse) provide supporting evidence for this concept. However, genetic analyses of DILI patient samples are needed to ultimately provide the proof-of-concept”[7].
Figures. Mechanisms of Drug-Induced Liver Injury and Factors related to the occurrence of DILI (used with permission from Oxford Press; reference [7])
To this end, Dr. Brett Howell and other colleagues at the Hamner-UNC Institute for Drug Safety Sciences (IDSS) developed an in-silico model of DILI ( the DILISym™ model)which is based on depletion of cellular ATP and reactive metabolite formation as indices of DILI.
Have there been Genetic Risk Factors identified for DILI?
Candidate-gene-associated studies (CGAS) have been able to identify several genetic risk factors for DILI including:
Uridine Diphosphate Glucuronosyltransferase 2B7 (UGT2B7): variant increased susceptibility to diclofenac-induced DILI
Adenosine triphosphate-binding cassette C2 (ABCC2) variant ABCC-24CT increased susceptibility to diclofenac-induced DILI
Glutathione S-transferase (GSTT1): patients with a double GSTT1-GSTM1 null genotype had a significant 2.7 fold increased risk of DILI from nonsteroidal anti-inlammatory agents, troglitazone and tacrine. GSTs are involved in the detoxification of phase 1 metabolites and also protect against cellular ROS.
Although these CGAS confirmed these genetic risk factors, Stefan Russman suggests a priori genome-wide association studies (GWAS) might provide a more complete picture of genetic risk factors for DILI as CGAS is limited due to
Candidate genes are selected based on current mechanisms and knowledge of DILI so genetic variants with no known knowledge of or mechanistic information would not be detected
Many CGAS rely on analysis of a limited number of SNP and did not consider intronic regions which may control gene expression
A priori GWAS have the advantage of being hypothesis-free, and although they may produce a high number of false-positives, new studies of genetic risk factors of ximelagatran, flucioxaciliin and diclofenac-induced liver injury are using a hybrid approach which combines the whole genome and unbiased benefits of GWAS with the confirmatory and rational design of CGAS[8-10].
Even though idiosyncratic DILI is rare, the severity, unpredictable onset, and unknown etiology and risk factors have prompted investigators such as Stefan Russmann from University Hospital Zurich and Ignazio Grattagliano from University of Bari to suggest:
Identification of risk factors for rare idiosyncratic hepatotoxicity requires special networks that contribute to data collection and subsequent identification of environmental as well as genetic risk factors for clinical cases of idiosyncratic DILI[11].
Therefore, a DILI network project (DILIN) had been developed to collect samples and detailed genetic and clinical data on IDILI cases from multiple medical centers. The project aims to identify the upstream and downstream genetic risk factors for IDILI[12]. Please see a SlideShare presentation here of the goals of the DILI network project.
Elevation in serum bilirubin during treatment with lapatinib and pazopanib are associated with UGT1A1 polymorphism related to Gilbert’s syndrome (a clinically benign syndrome)
Anecdotal evidence shows that polymorphisms of lapatinib and pazopanib metabolizing enzymes may contribute to differences seen in onset of DILI
Pazopanib-induced elevations of ALT correlate with HFE variants, suggesting alterations in iron transport may predispose to DILI
Note that these clinical findings were not evident from the preclinical tox studies. According to the European Medicines Agency assessment report for Tykerb states: “the major findings in repeat dose toxicity studies were attributed to lapatinib pharmacology (epithelial effect in skin and GI system. The toxic events occurred at exposures close to the human exposure at the recommended dose. Repeat-dose toxicity studies did not reveal important safety concerns than what would be expected from the mode of action”.
However, it should be noted that in high dose repeat studies in mice and rats, severe lethality was seen with hematologic, gastrointestinal toxicities in combination with altered blood chemistry parameters and yellowing of internal organs.
IAP Antagonists, Mechanism of Action, and Clinical Trials:
A few IAP antagonists which are in early stage development include:
Norvatis IAP Inhibitor LCL161: at 2012 San Antonia Breast Cancer Symposium, a phase 1 trial in triple negative breast cancer showed promising results when given in combination with paclitaxel.
Ascenta Therapeutics IAP inhibitor AT-406 in phase 1 in collaboration with Debiopharm S.A. showed antitumor efficacy in xenograft models of breast, pancreatic, prostate and lung cancer. The development of this compound is described in a paper by Cai et. al.
National Cancer Institute sponsored trials using antagonists of IAPs include
Phase II Study of Birinapant for Advanced Ovarian, Fallopian Tube, and Peritoneal Cancer (NCI-12-C-0191). Principle Investigator: Dr. Christina Annunziata. See the protocol summary. More open trials for this drug are located here. Closed trials including safety studies can be found here.
A Phase 1 non-randomized dose escalation study to determine maximum tolerated dose (MTD) and characterize the safety for the TetraLogic compound TL32711 had just been completed. Results have not been published yet.
Closed Clinical trials with the IAP antagonist HGS1029 in advanced solid tumors determined that weekly i.v. administration of HGS1029 reported a safety issue for primary outcome measures
A great review on IAP proteins and their role as regulators of apoptosis and potential targets for cancer therapy [14] can be found as a part of a Special Issue in Experimental Oncology “Apoptosis: Four Decades Later”. Human IAPs (inhibitors of apoptosis) consist of eight proteins involved in cell death, immunity, inflammation, cell cycle, and migration including:
In general, IAP proteins are directly involved in inhibiting apoptosis by binding and directly inhibiting the effector cysteine protease caspases (caspase 3/7) ultimately responsible for the apoptotic process [15]. IAPs were actually first identified in baculoviral genomes because of their ability to suppress host-cell death responses during viral infection [16]. IAP proteins are often overexpressed in cancers [17].
Apoptosis is separated into two pathways, defined by the initial stress or death signal and the caspases involved:
Extrinsic pathway: initiated by TNFα and death ligand FasLigand; involves caspase-8; process inhibited by IAP1/2
Intrinsic pathway: initiated by DNA damage, irradiation, chemotherapeutics; mitochondrial pathway involving caspase 9 and cytochrome c release from mitochondria; mitochondria also releases SMAC/DIABLO, which binds and inhibits XIAP (XIAP inhibits the Intrinsic apoptotic pathway.
The Curis IAP antagonist (and others) is a SMAC small molecule mimetic. It is interesting to note [18, 19] that IAP antagonists can result in death by
Apoptosis: an IAP antagonist in presence of competent TNFα signaling
Necrosis: seen with IAP inhibitors in cells with altered TNFα signaling or with presence of caspase inhibitors
IAPs are also involved in the regulation of signaling pathways such as:
NF-ΚB signaling pathway
NF-ΚB is a “rapid-acting” transcription factor which has been found to be overexpressed in various cancers. Under most circumstances NF-ΚB translocation to the nucleus results in transcription of genes related to cell proliferation and survival. NF-ΚB signaling is broken down in two pathways
Canonical: Canonical pathway can be initiated (for example in inflammation) when TNF-α binds its receptors activating death domains (TRADD)
Noncanonical: since requires new protein synthesis takes longer than canonical signaling. Can be initiated by other TNF like ligands like CD40
IAP1/2 is a negative regulator of the noncanonical NF-ΚB signaling pathway by promoting proteosomal degradation of the TRAF signaling complex. A wonderfully annotated list of NF-ΚB target genes can be found on the Thomas Gilmore lab site at Boston University at http://www.bu.edu/nf-kb/gene-resources/target-genes/ .
NF-ΚB has been considered a possible target for chemotherapeutic development however Drs. Veronique Baud and Michael Karin have pondered the utility of IAP antagonists as a good target in their review: Is NF-ΚB a good target for cancer therapy?: Hopes and pitfalls [20]. The authors discuss issues such that IAP antagonism induced both the classical and noncanonical NF-ΚB pathway thru NIK stabilization, resulting in stabilization of NF-ΚB signaling and thereby undoing any chemotherapeutic effect which would be desired.
AKT signaling
IAPs have been shown to interact with other proteins including a report that SIAP regulates AKT activity and caspase-3-dependent cleavage during cisplatin-induced apoptosis in human ovarian cancer cells and could be another mechanism involved in cisplatin resistance[21]. In addition there have been reports that IAPs can regulate JNK and MAPK signaling.
Therefore, IAPs are involved in CANONICAL and NONCANONICAL pathways.
IAPs can Regulate Pro-Inflammatory Cytokines
A recent 2013 JBC paper [22]showed that IAPs and their antagonists can regulate spontaneous and TNF-induced proinflammatory cytokine and chemokine production and release
IAP required for production of multiple TNF-induced proinflammatory mediators
IAP antagonism decreased TNF-mediated production of chemokines and cytokines
But increased spontaneous release of chemokines
In addition Rume Damgaard and Mads Gynd-Hansen have suggested that IAP antagonists may be useful in treating inflammatory diseases like Crohn’s disease as IAPs regulate innate and acquired immune responses[23].
Toxicity profiles of IAP antagonists
NOTE: In a paper in Toxicological Science from 2012[24], Rebecca Ida Erickson form Genentech reported on the toxicity profile of the IAP antagonist GDC-0152 from a study performed in dogs and rats. A dose-dependent toxicity profile from i.v. administration was consistent with TNFα-mediated toxicity with
Elevated plasma cytokines and an inflammatory leukogram
Increased serum transaminases
Inflammatory infiltrate and apoptosis/necrosis in multiple tissues
At week four after initiation of sorafenib treatment, the patient noticed increasing fatigue, malaise, gastrointestinal discomfort and abdominal rash. Although treatment was discontinued, jaundice developed and blood test revealed an acute hepatitis with
Elevated serum ALT
Elevated serum alkaline phosphatase
Increased prothrombin time
Increased LDH
…elevated levels seen in the case with the aforementioned IAP antagonist. Autopsy revealed
Lobular hepatitis
Mononuclear cell infiltrate
Hepatocyte necrosis
These findings are in line with a drug-induced inflammation and IDILI. In addition to hepatotoxicity, renal insufficiency developed in this patient. The authors had suggested the death was probably due to “an idiosyncratic allergic reaction to sorafenib manifesting as hepatotoxicity with associated renal impairment”. The authors also noted that genome wide association studies of idiosyncratic drug-induced liver injury support involvement of major histocompatibility complex (MHC) polymorphisms[26]. MHC involvement has also been associated with lapatanib and pazopanib hepatotoxicity [27, 28].
Curis has been involved in another novel oncology therapeutic, a first in class.
As an additional reference, the FDA National Center for Toxicological Research has developed THE LIVER TOXICITY KNOWLEDGE BASE (LTKB).
“The LTKB is a project designed to study drug-induced liver injury (DILI). Liver toxicity is the most common cause for the discontinuation of clinical trials on a drug, as well as the most common reason for an approved drug’s withdrawal from the marketplace. Because of this, DILI has been identified by the FDA’s Critical Path Initiatives as a key area of focus in a concerted effort to broaden the agency’s knowledge for better evaluation tools and safety biomarkers.”
The 2 deaths, due to acute liver failure, occurred in patients treated in Kazakhstan and Russia.
Two children with spinal muscular atrophy (SMA) have died after being treated with onasemnogene abeparvovec (Zolgensma; Novartis) from acute liver failure, a known safety risk of the therapy.1
Novartis has updated the FDA and other regulatory agencies in countries that Zolgensma is approved in, including Russia and Kazakhstan, where the deaths occurred. The company will also update the labeling of Zolgensma to include the deaths.
“While this is important safety information, it is not a new safety signal and we firmly believe in the overall favorable risk/benefit profile of Zolgensma, which to date has been used to treat more than 2300 patients worldwide across clinical trials, managed access programs, and in the commercial setting,” Novartis said in an emailed statement to BioPharma Dive.2
Zolgensma’s labeling includes the risk of liver injury and instructs clinicians to assess liver function before treatment and to manage liver enzyme counts with steroid treatment. The 2 deaths occurred 5 to 6 weeks after the one-time infusion and 1 to 10 days after corticosteroid treatment was tapered, according to an initial report from Stat News.1
An FDA advisory committee meeting that took place last fall identified risks of adeno associated virus (AAV) gene therapies including, specifically, Zolgensma.2 The committee recommended caution, but nothing that would hinder gene therapy development.
Zolgensma, which was approved in the US in May 2019, just recently demonstrated further positive data from SPR1NT (NCT03505099), a phase 3 multicenter, single-arm trial on its effect in presymptomatic children with SMA in 2 articles published in Nature Medicine.3,4
All children in both the type 1 and type 2 cohorts achieved the ability to independently sit and most achieved other age-appropriate milestones including standing and walking. None of the children in the study required respiratory support or nutritional support, and there were no serious treatment-related adverse events observed.
“The robust data from both the 2- and 3-copy SPR1NT cohorts are being published together for the first time, further supporting the significant and clinically meaningful benefit of Zolgensma in presymptomatic babies with SMA,” Shephard Mpofu, MD, SVP, chief medical officer, Novartis Gene Therapies, said in a previous statement.5 “When treated with Zolgensma prior to the onset of symptoms, not only did all 29 patients enrolled in SPR1NT survive, but were thriving—breathing and eating on their own, with most even sitting, standing, and walking without assistance.”
3. Strauss KA, Farrar MA, Muntoni F, et al. Onasemnogeneabeparvovec for presymptomatic infants with two copies of SMN2 at risk for spinal muscular atrophy type 1: the Phase III SPR1NT trial. Nat Med. Published online June 17, 2022. doi:10.1038/s41591-022-01866-42
4. Strauss KA, Farrar MA, Muntoni F, et al. Onasemnogeneabeparvovec for presymptomatic infants with three copies of SMN2 at risk for spinal muscular atrophy: the Phase III SPR1NT trial. Nat Med. Published online June 17, 2022.doi: 10.1038/s41591-022-01867-3
5. Novartis announces Nature Medicine publication of Zolgensma data demonstrating age-appropriate milestones when treating children with SMA presymptomatically. News release. Novartis. June 17, 2022. https://firstwordpharma.com/story/5597735
2. Waring JF, Liguori MJ, Luyendyk JP, Maddox JF, Ganey PE, Stachlewitz RF, North C, Blomme EA, Roth RA: Microarray analysis of lipopolysaccharide potentiation of trovafloxacin-induced liver injury in rats suggests a role for proinflammatory chemokines and neutrophils. The Journal of pharmacology and experimental therapeutics 2006, 316(3):1080-1087.
6. Seki E, Brenner DA, Karin M: A liver full of JNK: signaling in regulation of cell function and disease pathogenesis, and clinical approaches.Gastroenterology 2012, 143(2):307-320.
8. Kindmark A, Jawaid A, Harbron CG, Barratt BJ, Bengtsson OF, Andersson TB, Carlsson S, Cederbrant KE, Gibson NJ, Armstrong M et al: Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis. The pharmacogenomics journal 2008, 8(3):186-195.
9. Aithal GP, Ramsay L, Daly AK, Sonchit N, Leathart JB, Alexander G, Kenna JG, Caldwell J, Day CP: Hepatic adducts, circulating antibodies, and cytokine polymorphisms in patients with diclofenac hepatotoxicity. Hepatology 2004, 39(5):1430-1440.
10. Daly AK, Aithal GP, Leathart JB, Swainsbury RA, Dang TS, Day CP: Genetic susceptibility to diclofenac-induced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology 2007, 132(1):272-281.
13. Spraggs CF, Xu CF, Hunt CM: Genetic characterization to improve interpretation and clinical management of hepatotoxicity caused by tyrosine kinase inhibitors. Pharmacogenomics 2013, 14(5):541-554.
14. de Almagro MC, Vucic D: The inhibitor of apoptosis (IAP) proteins are critical regulators of signaling pathways and targets for anti-cancer therapy. Experimental oncology 2012, 34(3):200-211.
15. Deveraux QL, Takahashi R, Salvesen GS, Reed JC: X-linked IAP is a direct inhibitor of cell-death proteases. Nature 1997, 388(6639):300-304.
18. Laukens B, Jennewein C, Schenk B, Vanlangenakker N, Schier A, Cristofanon S, Zobel K, Deshayes K, Vucic D, Jeremias I et al: Smac mimetic bypasses apoptosis resistance in FADD- or caspase-8-deficient cells by priming for tumor necrosis factor alpha-induced necroptosis. Neoplasia 2011, 13(10):971-979.
19. He S, Wang L, Miao L, Wang T, Du F, Zhao L, Wang X: Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell 2009, 137(6):1100-1111.
21. Asselin E, Mills GB, Tsang BK: XIAP regulates Akt activity and caspase-3-dependent cleavage during cisplatin-induced apoptosis in human ovarian epithelial cancer cells. Cancer research 2001, 61(5):1862-1868.
22. Kearney CJ, Sheridan C, Cullen SP, Tynan GA, Logue SE, Afonina IS, Vucic D, Lavelle EC, Martin SJ: Inhibitor of apoptosis proteins (IAPs) and their antagonists regulate spontaneous and tumor necrosis factor (TNF)-induced proinflammatory cytokine and chemokine production. The Journal of biological chemistry 2013, 288(7):4878-4890.
23. Damgaard RB, Gyrd-Hansen M: Inhibitor of apoptosis (IAP) proteins in regulation of inflammation and innate immunity. Discovery medicine 2011, 11(58):221-231.
25. Fairfax BP, Pratap S, Roberts IS, Collier J, Kaplan R, Meade AM, Ritchie AW, Eisen T, Macaulay VM, Protheroe A: Fatal case of sorafenib-associated idiosyncratic hepatotoxicity in the adjuvant treatment of a patient with renal cell carcinoma. BMC cancer 2012, 12:590.
28. Xu CF, Reck BH, Goodman VL, Xue Z, Huang L, Barnes MR, Koshy B, Spraggs CF, Mooser VE, Cardon LR et al: Association of the hemochromatosis gene with pazopanib-induced transaminase elevation in renal cell carcinoma. Journal of hepatology 2011, 54(6):1237-1243.
Other articles on the site about Toxicology and Pharmacology of New Classes of Cancer Chemotherapy include:
Last August, UPenn scientists announced the dramatic results of a tiny clinical trial of their immunotherapy approach, describing long-lasting remissions in leukaemia patients for whom standard therapies had stopped working. Trials are also underway for other leukaemias and for lymphoma, mesothelioma, myeloma and neuroblastoma, according to the university.
The therapy developed by UPenn’s Carl June is complicated. Vaccines prompt a patient’s immune system to attack dangerous cells through an approach, called chimeric-antigen-receptor immunotherapy – a genetically redesigned immune cells for a more powerful attack. In this therapy first, blood is collected from leukaemia patients and exposed to substances that activate T cells, powerful cells that launch and coordinate immune attacks. Next, the T cells are genetically modified to recognize and attack leukaemia cells. Finally, the altered cells are returned to the patient, where they are expected to proliferate until the cancer cells are gone.
Drug giant Novartis is making a multimillion dollar bet that a patient’s immune system can be cancer’s worst enemy. It is teaming up with scientists at the University of Pennsylvania (UPenn) in Philadelphia to develop and manufacture cancer immunotherapies.
In the US$20-million collaboration, announced today, Novartis, which is based in Basel, Switzerland, will get exclusive worldwide rights to these technologies.
Foundation Medicine and Novartis have reached a 3 year agreement to use Foundation’s clinical grade, next-generation sequencing to support the drug firm’s clinical oncology programs. The agreement builds on a 2011 deal between the firms and calls for the use of Foundation Medicine’s molecular information platform across many of Novartis’ Phase 1 and Phase 2 oncology clinical programs. The initial collaboration generated “very interesting” data, and this type of tumor genomic profiling has become an important part of Novartis’ clinical trials, Foundation Medicine said.
Foundation Medicine added that it may develop additional diagnostic products from the partnership.
“The comprehensive molecular assessment of Novartis’ Oncology clinical trial samples is expected to help to bring potentially lifesaving therapies to the right patients more quickly, and we expect that the wealth of molecular information will help fundamentally improve the way cancer is understood and treated,” Michael Pellini, president and CEO of Foundation Medicine, said in a statement.
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