Elusive Target: A Rundown of the Drug Pipeline for Systemic Lupus Erythematosus
Systemic lupus erythematosus is a heterogeneous disease that requires a customized approach to its management. Therapies range from nonsteroidal anti-inflammatory drugs to one of any number of immunomodulators or biologics. However, the clinical community has yet to arrive at a perfect therapy or even a perfect combination of therapies.
“Every patient with lupus is different,” Ziv Paz, MD, MPH, MSc, of the Division of Rheumatology & Lupus Center at Beth Israel Deaconess Medical Center and Harvard Medical School, said in an interview with Healio Rheumatology. “All of the lupus patients are grouped together, but there are multiple subgroups depending on whether the skin, kidney, heart, brain or other systems are impacted. We do not yet fully understand what is driving lupus, or how one patient is different from the other. This makes it difficult to find targeted therapies.”
Researchers have spent decades chasing a cure to systemic lupus erythematosus (SLE), according to Paz.
“Almost every branch of the immune system is involved in the pathophysiology of SLE, including B cells and T cells. We try to block different cytokines, receptors and signal transduction pathways. We keep trying the obvious,” he said.
Despite the obstacles, there is reason for optimism in the SLE pipeline, according to H. Michael Belmont, MD, professor in the Department of Medicine, associate director of clinical affairs in the Division of Rheumatology and medical director of the Hospital for Joint Diseases at NYU Langone Medical Center.
“We are understanding the biology of the disease better,” he said. “We are nailing down our understanding of the autoreactive processes that contribute to SLE,” he said.
Paz agreed, but with qualifications.
“We know more about this disease every year, which leads to the development of new lines of treatment,” Paz said. “But it is an uphill battle. The problem with lupus as a disease is that we still do not know exactly what is going on in terms of pathogenesis and how to explain the versatility of the disease.”
This unsteady journey toward understanding the disease has fueled the pipeline. Strides have been made, but at great cost and during a long period of time. An example is the FDA approval of belimumab, an inhibitor of the B lymphocyte stimulator (BLyS) protein. In 2011, it became the first SLE therapy approved in 50 years. Other treatments targeting the same pathway — namely blisibimod and atacicept — are in development.
“Some therapies have shown great success in animal models, but no activity in humans,” Paz said. “Most of these trials are stopping between phase 1 and phase 2.”
Similar things could be said for other drugs and targets in the pipeline right now, including those that target interferon-gamma (IFN-gamma) or interferon-alpha (IFN-alpha); Toll-like receptors (TLRs); B-cell activating factor (BAFF) antagonists; CD20 inhibitors; and approaches ranging from statins to tetrahydrocannabinol (THC) metabolites.
In this Cover Story,Healio Rheumatology takes a look at some of the drugs in the SLE pipeline.
Richard Alan Furie, MD, chief of the Division of Rheumatology at Northwell Health, an investigator at The Feinstein Institute for Medical Research and professor of Medicine at Hofstra Northwell School of Medicine, and colleagues, conducted a phase 2 study with anifrolumab, an anti-IFN-alpha receptor monoclonal antibody, in a cohort of 305 patients with moderate to severe SLE. Findings from the randomized, double-blind, placebo-controlled study were presented at last year’s American College of Rheumatology Annual Meeting.
Eligible participants received the study drug (300 mg or 1000 mg) intravenously or placebo every 4 weeks for 48 weeks. Composite SLE responder index (SRI) response at day 169 with sustained reduction of oral corticosteroid use (,10 mg/day and , day-1 dose maintained between days 85 and 169) served as the primary outcome measure. The two secondary endpoints, which were assessed at day 365, included a composite of SRI at day 365 with a reduction of oral corticosteroid use between days 281 and 365 and a reduction of corticosteroids to less than or equal to 7.5 mg/day by day 365 among patients treated with greater than or equal to 10 mg/day at baseline.
The primary endpoint was achieved by 17.6% of those treated with placebo compared with 34.3% of patients treated with 300 mg anifrolumab (AstraZeneca), (P = 0.014) and 28.8% of those treated with 1,000 mg anifrolumab (P = 0.063). Day 365 results indicated the secondary SRI endpoint was reached in 25.5% of placebo patients compared with 51.5% of patients in the 300-mg arm (P < 0.001) and 38.5% of patients in the 1,000-mg arm (P = 0.048).
The 300-mg dose was associated with significant improvements in oral corticosteroid use at day 365 compared with placebo, and showed benefit across a number of other outcomes. Both doses of anifrolumab yielded suppression of 21 interferon-related genes. The adverse event profile of the drug was notable for a higher rate of shingles as well as the “flu.”
“Anifrolumab significantly reduced disease activity compared with [placebo] across multiple clinical endpoints,” the researchers concluded. “Enhanced effects in IFN high patients support the pathobiology of this treatment strategy. The lack of dose response can be explained by the nearly similar degrees of IFN gene signature inhibition achieved with the two anifrolumab doses. These data strongly support further development of anifrolumab.”
“Many patients with SLE have an IFN signature on blood testing, so this approach makes sense,” Janet E. Pope MD, MPH, FRCPC, professor of medicine at Western University and division head of rheumatology at St. Joseph’s Hospital in London, Ontario, Canada, said in an interview with Healio Rheumatology. “Anifrolumab seemed to work better at 300 mg than 1000 mg, which is a bit unusual that a higher dose gave less, not the same or more, of an improvement.”
Furie said researchers are recruiting for a phase 3 trial. Belmont noted the drug had the most dramatic impact on the skin, but this was not the only effect.
“The most impressive results were in cutaneous lupus erythematosus,” Belmont said. “There were also signs of efficacy with more serious organ involvement, including nephritis. We should be encouraged by these findings.”
Paz added that “this drug is a monoclonal antibody which targets type 1 IFN. The natural idea was to target this specific cytokine. These results justify moving to phase 3.”
The adverse event profile is encouraging, according to Paz.
“We do not see many side effects compared with the placebo group,” he said. “I expect we will see clinical effectiveness in a phase 3 setting.”
In another study involving an anti-INF-alpha monoclonal antibody, Khamashta and colleagues investigated sifalimumab (MedImmune) in a cohort of 431 patients with moderate to severe SLE. The phase 2b, randomized, double-blind, placebo-controlled study involved patients treated with 200 mg, 600 mg or 1200 mg of the study drug, or placebo, intravenously along with standard-of-care medications. The SRI at 52 weeks served as the primary endpoint. The primary endpoint was reached by 45.4% of patients in the placebo arm compared with 58.3% of patients in the 200-mg arm, 56.5% of patients in the 600-mg arm and 59.8% of those in the 1200-mg arm. However, Furie said the superior outcome with anifrolumab has led to the decision to develop just anifrolumab.
The researchers also observed improvements in Cutaneous Lupus Erythematosus Disease Area and Severity Index score (in the 200-mg and 1200-mg groups), physician’s global assessment (in the 600-mg and 1200-mg groups) and the BILAG-based composite lupus assessment (in the 1200-mg group). Swollen and tender joints also improved, as did the SLE Disease Activity Index 2000. Serious adverse event rates were 17.6% for placebo and 18.3% for the study drug. Sifalimumab increased the likelihood of herpes zoster infection, the results showed.
AMG 811 (Amgen) is another monoclonal antibody, anti-IFN-gamma IgG1, which was most recently investigated by Chen and colleagues. They investigated how exposure to the drug changes serum IFN-gamma and IP-10 (CXCL10) by creating a pharmacokinetic and pharmacodynamics model. Results showed that for an average SLE patient, the linear clearance of AMG 811 was 0.176 L/day. The central volume of distribution was 1.48 L, while the peripheral volume of distribution was 2.12 L. Body weight correlated with linear clearance, as well as the two measures of volume of distribution.
“The largest observed reduction of serum CXCL10 concentration was achieved at the highest AMG 811 dose tested (180 mg SC),” the researchers concluded. “This model enables simulations of AMG 811 [pharmacokinetic-pharmacodynamic] profiles under various dosing regimens to support future clinical studies.”
“This drug is in the early phase trials and not yet studied for its clinical effectivity,” Paz said.
Gregg J. Silverman, MD, professor in the Departments of Medicine and Pathology and co-director of the Musculoskeletal Center of Excellence at NYU Langone Medical Center, put the IFN-alpha and IFN-gamma approaches into context.
“Starting several decades ago, we have had mounting evidence that patients with lupus often have high circulating blood levels of type 1 IFN and there are also increases of proteins that are induced by [it],” he said. “The question has always been: Does this correlation prove causation?”
Silverman said we have wondered whether IFN plays a central role in the pathogenesis of SLE, but it also may simply be a bystander signature. This fueled attempts to target type 1 IFN.
“The result with antibodies that target the IFN cytokines sometimes showed minor effects but other times, not effects at all, biologically or clinically,” he said. “The ‘glass half full’ people said it is worth further investigation, we just need a better antibody. The ‘glass half empty’ people said it was not a cause, but an effect and might not be important.”
Regardless, Silverman said continued targeting of IFN pathways could lead to further breakthroughs. The recent results with anifrolumab (AstraZeneca), an antibody to the IFN receptor, have shown both biologic activity and these early studies have shown clinical benefits for the treatment of a small group of lupus patients. However, Silverman raised a concern with this approach.
“It looked like the higher the dose of the IFN blocker, the higher the frequency of herpes zoster (shingles cases) you get,” he said. “Again, this is a good news-bad news story. It validates that IFN is not a bystander or minor player, but now seems more likely to be a central mediator of lupus. The bad news is that this may be an early indicator that there will be significant infection side effects with more powerful IFN-alpha blockers.”
For Belmont, recognizing the role of the IFN-gamma cytokine in stimulating immune response in B cells, T cells and macrophages offers a reason to believe based on animal and human studies that inhibiting IFN-gamma will be useful.
Stohl and colleagues conducted a first-in-man clinical study of blisibimod (Anthera Pharmaceuticals), a selective peptibody antagonist of the BAFF cytokine, also known as a BLyS, that was published in August 2015. The aim was to assess safety, tolerability and pharmacokinetic and pharmacodynamic profiles of the drug compared with placebo. The study included 54 patients in phase 1a, where blisibimod or placebo was administered in a single dose 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg or 3 mg/kg subcutaneously or 1 mg/kg, 3 mg/kg or 6 mg/kg intravenously and 63 patients in phase 1b, in which four weekly doses of blisibimod or placebo were administered at 0.3 mg/kg, 1 mg/kg or 3 mg/kg subcutaneously or at 6 mg/kg intravenously. A decrease in the number of naïve B cells of 24% to 76% was reported in the blisibimod group, as was a transient relative increase in the memory B-cell compartment, the strongest effect of which was found on IgD(-)CD27+, according to the findings.
T cells or natural killer cells did not change in the study drug group. With time, memory B cells returned to baseline levels. The result was that at 160 days after the first dose, a calculated 30% reduction in total B cells occurred. Among patients treated subcutaneously, pharmacokinetic results showed slow absorption, dose-proportional exposure from 0.3 mg/kg through 3.0 mg/kg subcutaneously and 1 mg/kg through 6 mg/kg intravenously, linear pharmacokinetics for a 1.0 mg/kg to 6.0 mg/kg dose range and accumulation ratios that ranged between 2.21 and 2.76. No association was reported between the relative increase in memory B cells and safety signals. Comparable adverse event rates, along with anti-blisibimod antibodies and clinical laboratory abnormalities, were reported in the study drug and placebo groups.
“Blisibimod changed the constituency of the B-cell pool, and single and multiple doses of blisibimod exhibited approximate dose-proportional pharmacokinetics across the dose range 1 [mg/kg] to 6 mg/kg,” the researchers concluded. “The safety and tolerability profile of blisibimod in SLE was comparable with that of placebo. These findings support further studies of blisibimod in SLE and other B cell-mediated diseases.”
“We already have one approved BAFF antagonist in Benlysta (belimumab, GSK)” Furie said. “Eventual approval of blisibimod would mean a second drug in the same class.”
“The approval of Benlysta by the FDA was historic as this was the first drug approved for SLE based on traditional randomized placebo controlled studies,” he said. “The complexity of lupus and the challenges of drug development have been underrated, but it is just a matter of time before additional drugs are approved.”
Cogollo and colleagues wrote a retrospective paper about trials of atacicept (Merck Serono) in SLE. They stressed the BLyS and APRIL pathways should be areas of further investigation, but acknowledged that discouraging mortality results have been reported. They suggested a 150-mg dose of the drug may be worth more study.
“With regard to safety concerns, careful interpretation of the data is reassuring,” they wrote. “The results of the atacicept trial in patients with [lupus nephritis] LN suggest that minimizing the use of concurrent immunosuppressive medications, notably mycophenolate, may diminish the risk of infection while improving clinical response.”
“Atacicept inhibits two key growth factors for B cells in the BLyS pathway, BlyS and APRIL” Furie said. “Whereas Benlysta and blisibimod inhibit BlyS, atacicept inhibits both BLyS and APRIL. Atacicept is a recombinant receptor identical to the TACI receptor found on the surface of B cells. This approach continues in trials.”
Belmont said the BLyS inhibitor belimumab has been approved for patients without renal or neuropsychiatric manifestations.
“However, there is reason to believe that inhibiting BLyS will have benefit in renal nephritis with a generally favorable toxicity profile,” he said.
Wu and colleagues suggested a growing body of evidence supports the idea that TLRs “are implicated in the pathogenesis of autoimmune diseases by recognition of self-molecules.” Results in mouse models and human observational studies have suggested TLR2/4, TLR5, TLR3 and TLR7/8/9 may be involved in the pathogenesis of SLE. In addition, MyD88, IRAKs and IFN-alpha are downstream proteins that may serve as targets for therapeutic intervention.
“Numerous antagonists targeting TLR signaling, including oligonucleotides, small molecular inhibitors and antibodies, are currently under preclinical studies or clinical trials for SLE treatment,” they wrote. “Moreover, the emerging new manipulation of TLR signaling by microRNA (miRNA) regulation shows promise for the future treatment of SLE.”
According to Furie, TLR inhibitors have been studied in psoriasis, but only once in SLE. Unfortunately, the one study did not achieve its primary endpoint, a pharmacodynamic outcome. Paz described the approach as a unique concept that is on the cutting-edge of SLE therapy.
“Every day, it seems like, we learn about a new TLR receptor,” he said. “TLR receptors are designed to identify shared sequences of microorganisms and enhance the immune response against these. The blockage of these receptors offers an opportunity to halt the immune response, especially in light of new data that suggest the role of these receptors in autoimmunity.”
Belmont broke down the mechanism of action of this approach.
“Our current understanding is that lupus results from a genetic predisposition, and likely as yet unidentified environmental trigger,” he said. “As a result of the trigger chromatin-containing immune complexes interact with Toll-like receptors, including TLR9. As a consequence, immune cells increase type 1 alpha IFN production. So it is rational to believe that TLR inhibitors working upstream in this autoreactive immune response will be effective.”
Pope built on this point. “TLR agonists are important in host immunity mounting a response to infections,” she said. “TLR7 and TLR9 are important in the production of autoantibodies, including those produced in systemic autoimmune diseases.”
Topical TLR7 can has been shown to cause autoimmune lupus-like disease in mice, according to Pope. “Activation of TLRs can increase type 1 IFN,” she said. “TLRs, especially TLR7, could be a target in SLE, including the possible development of a vaccine. However, this method is not at all in the near future for SLE patients.”
Belmont said the CD20 story begins with rituximab. In the LUNAR trail, Rovin and colleagues studied the drug in 144 patients with class III or IV lupus. Patients were randomly assigned 1000 mg of the study drug or placebo on days 1, 15, 168 and 182. Rituximab (Rituxan, Genentech/Biogen Idec), showed no significant clinical benefit at 52 weeks, according to the results. “The combination of rituximab with [mycophenolate mofetil] and corticosteroids did not result in any new or unexpected safety signals,” the researchers wrote.
For Silverman, the combination of rituximab with other agents was key to the failure of the study. The other issue was the duration of follow-up. Despite setbacks, the road for CD20 in SLE is not over, he said.
“This is only expressed in a subset of B lymphocytes,” he said. “Obinutuzumab (Gazyva, Genentech) has higher activity and greater patient penetration. Chances are it will kill more B cells that are deep in our tissue, cells that cause the worst effects of lupus. In many ways, this drug is new and improved and more active.”
Paz said obinutuzumab has not been studied in SLE.
“If you block the CD20, you block production of the autoantibodies and reduce the population of B cells,” he said.
Furie, who was an investigator on the rituximab trial, is cautiously optimistic about this approach.
“Clinicians use rituximab despite the negative trials,” he said. “It will be interesting to study the more potent inhibitor. There are still many believers in this strategy.”
He added there are several ongoing studies with rituximab, as well as studies evaluating the sequential use of rituximab followed by belimumab.
In 2013, Suchard and colleagues investigated a monovalent CD28 domain antibody for efficacy and safety in the preclinical setting. They described the anti-human CD28 receptor antagonist domain antibodies (dAbs) that are specific to CD28 in humans, according to the results.
“These dAbs are potent inhibitors of T-cell activation, with an EC50 of 35 ± 14 ng/mL for inhibition of proliferation,” they wrote. “The EC50 of 53 ± 11 ng/mL in an ex vivo CD28 receptor occupancy assay corresponds with in vitro functional activity, suggesting a direct correlation.”
Findings suggest that this dAb showed pharmacodynamic activity in cynomolgus monkeys, according to the researchers. The evidence was measured in terms of a T-cell-dependent Ab inhibition without depletion of T cells or release of cytokines.
“Furthermore, there was a strong correlation between systemic exposure, duration and extent of CD28 receptor occupancy, and pharmacodynamic activity,” the researchers wrote. “Taken together, these data support clinical evaluation of this novel anti-CD28 dAb for the treatment of autoimmune diseases.”
“The concept [of CD28] is T-cells signaling B cells,” Belmont said. “This is a costimulatory pathway. Antigen-presenting cells give an activation signal to autoreactive T cells. By blocking CD28 and antagonizing the antigen-presenting cell, signaling an autoreactive T cell, you can prevent the subsequent production of autoantibodies that characterize lupus.”
Pope said CD28 (costimulatory signaling inhibition) drug abatacept may have a future in SLE.
“Trials to date with abatacept did not have positive results in lupus nephritis,” she said. “However, there is a trial of abatacept in lupus inflammatory arthritis that is recruiting patients.”
A 52-week phase 2b trial is underway to investigate 200 mcg IPP-201101 or Lupuzor. The drug is a polypeptide corresponding to the sequence 131-151 of the 70k snRNP protein with a serine phosphorylated in position 140. It is in the recruiting phase now, and the primary endpoint is SRI at week 52.
Belmont said Lupuzor (ImmuPharma) is not a monoclonal antibody and it has a distinct mechanism of action.
“It is an inhibitor of intracellular signaling of autoreactive immune cells,” he said. “The peptide provokes a weaker activation of autoreactive T-helper cells inhibiting their help of autoantibody producing B cells.”
“The phase 2 human trial showed no serious toxicity signal,” he added.
Corbus Pharmaceuticals recently announced that ajulemic acid (AB-III-56, HU-239, IP-751, CPL 7075, CT-3, Resunab), a synthetic cannabinoid derivative of the non-psychoactive THC metabolite11-nor-9-carboxy-THC, will be used in a phase 2 trial in a cohort of 100 patients with SLE who have active disease. Early animal models have shown efficacy at reducing inflammation. Patients in the trial will be treated placebo or one of three doses of the drug for 84 days, with 28 days of follow-up, according to a press release on the Corbus web site.
“They are looking at anti-inflammatory effects,” Silverman said of the ajulemic acid approach. “This is a pathway involving inflammation, but also activity related to fibrosis.”
He noted that in many rheumatic diseases, the pathology is that as inflammation resolves, fibrosis or scarring remains.
“The progression to fibrosis and scarring may be as important as the actual organ injury and dysfunction,” he said. “This certainly is a novel approach. The question is whether it will be effective.”
Janus kinase (Jak) inhibitors may be another fruitful area of research, according to Silverman. “Other investigators have targeted Jak 1, 2 and 3,” he said. “Cyk2 may be another target. It may be useful in inhibiting IFN. It is in early trials in rheumatoid arthritis now, we will see how those studies go.”
Yu and colleagues investigated the anti-inflammatory and cardiovascular protective effects of statins in a cohort of 4,095 patients with SLE and hyperlipidemia. The population-based study was conducted using data from Taiwan National Health Insurance Research Database between 1997 and 2008. The trial included 935 pairs of patients. Multivariable analysis results indicated all-cause mortality was lower in statin users compared with non-statin users. A more significant decrease in all-cause mortality was reported in high-dose statin users. Coronary artery disease, cardiovascular disease and end-stage renal disease also were reduced in statin users.
“Statin therapy in SLE patients with hyperlipidemia may reduce the risk of mortality, cardiovascular disease and [end-stage renal disease],” the researchers concluded. “The effect of statins needs to be demonstrated in large prospective studies with long-term follow-up.”
“We are learning the hard way about the true indicators of lupus, the true activity of lupus,” Furie said. “We may need more than one drug to treat this disease.”
This point was echoed by Paz. “I think the solution will be in combining approaches,” he said. “Multiple drugs work at different targets.”
It is hard to predict which combinations will work best, according to Paz. “Different patients have different underlying abnormal immune processes that drive their disease and their unique manifestations. We need to integrate patient-specific molecular and immunological data in our decisions about treatment,” he said. “We are still not at that level of intervention.”
For Pope, clinical trial design is critical.
“For new agents to be successful, the outcome measurements in SLE may need to be revamped,” she said. “There is a partial response index, but if the traditional SLE Disease Activity Index is used, then important results can be missed. For instance, if someone with SLE in a trial has a marked improvement of their inflammatory rash or arthritis, but the rash is not gone or the arthritis still is present in two joints, then there is no response recorded. The instruments to detect changes in SLE during trials should be ‘borrowed’ from other trials, such as rheumatoid arthritis or psoriasis.”
Belmont remains optimistic. “In addition to our increased understanding of the disease, I think the future includes use of genomics and proteonomics,” he said. “Patients will be increasingly clustered by clinical phenotype, serologic phenotype and genetic phenotypes allowing for selection of the most appropriate biological treatment targeted to the individual patient’s most relevant autoreactive processes.”
For Silverman, not long ago, lupus was an orphan disease. “Because it was an orphan disease, it was not eligible for drug development,” he said. “Now, we see it as a great unmet need. This will continue to drive research.”
How far research will go and how long it will take remains uncertain, sources said.
“I hope 20 years from now, we will be able to look back on this time as when we figured out how to attack this disease,” Paz said. – by Rob Volansky
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- Furie RA, et al. Abstract #3223. Presented at: American College of Rheumatology Annual Meeting; Nov. 7-11, 2015; San Francisco.
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- Rovin BH, et al. Arthritis Rheum. 2012;doi:10.1002/art.34359.
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- Wu YW, et al. Acta Pharmacologica Sinica. 2015;doi:10.1038/aps.2015.91.
- Yu HH, et al. Atherosclerosis. 2015;doi:10.1016/j.atherosclerosis.2015.08.030.
- For more information:
- H. Michael Belmont, MD, can be reached at 333 East 38th St., 4th Floor, New York, NY 10016; email: email@example.com.
- Richard Alan Furie, MD, can be reached at 350 Community Dr., Manhasset, NY 11030; email: firstname.lastname@example.org.
- Ziv Paz, MD, MPH, MSc, can be reached at 110 Francis St., Suite 4B, Boston, MA 02215; email: email@example.com.
- Janet E. Pope MD, MPH, FRCPC, can be reached at St. Joseph’s Health Care, 268 Grosvenor St., London, ON N6A 4V2 Canada; email: firstname.lastname@example.org.
- Gregg J. Silverman, MD, can be reached at 450 East 29th St., New York, NY 10016; email: email@example.com.
Disclosures: Belmont and Paz report no relevant financial disclosures. Furie reports he is a consultant, investigator and receives research support from AstraZeneca, Biogen Idec, Bristol-Myers Squibb, Boehringer-Ingelheim, Celgene, Eli Lilly, Exagen, Genentech/Roche, GlaxoSmithKline, MedImmune, Pfizer, Mallinckrodt Pharmaceuticals, Sanofi and UCB Pharma; he is a consultant for Chugai, Estrela (Janssen) and EMD Merck; is an investigator for and receives research support from Takeda; and is a committee member of the American College of Rheumatology, Lupus Foundation of America, Lupus Alliance of America, SLE Foundation, Alliance for Lupus Research and The Lupus Academy. Pope reports she is a consultant for Amgen, AbbVie, Actelion, Bristol-Myers Squibb, Celgene, GSK, Hospira, Janssen, Eli Lilly, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi, Teva and UCB Pharma. Silverman reports he is a consultant for Celgene, Genentech, Eli Lilly, Pfizer and Roche.