Category Archives: lupus

Systemic lupus erythematosus, lupus nephritis.

Brodalumab for Psoriasis – what a mess

Let’s agree that the headline “Suicide Stunner” – penned by John Carroll for FierceBiotech – can never auger anything but very bad news, and never more so then when it is used to describe clinical trial results. Released on the Friday before the long US holiday weekend, bookended to the announcement of positive news on it’s PSCK9 program, Amgen stated that it was walking away from an expensive co-development program with AstraZeneca, basically washing it’s hands of the anti-IL-17 receptor (IL-17R) antibody brodalumab because of suicidal tendencies and actual suicides that occurred in the Phase 3 psoriasis trials. Brodalumab is under development for the treatment of plaque psoriasis, psoriatic arthritis and axial spondyloarthritis. Amgen stated that they believed that the approval label for brodalumab would contain warning language regarding suicide risk, and this would limit the success of the drug. By using such language while pulling the plug Amgen has essentially put AstraZeneca in the position of having to prove to the FDA that there is no suicide risk.

Holy crap.

Note here that we are not talking about a psychiatric drug, where the risk of suicide might be the consequence of trying to re-align an aberrant central nervous system. Instead we are talking about a drug that targets autoimmune disorders by blocking the action of T cells. This is not a biology linked to psychiatric health, at least not as we understand it today (more on this later).

Backing up: in April 2012, AstraZeneca and Amgen announced a collaboration to jointly develop and commercialize five clinical-stage monoclonal antibodies from Amgen’s inflammation portfolio: AMG 139, AMG 157, AMG 181, AMG 557 and brodalumab (aka AMG 827). The drivers for the collaboration were Amgen’s biologics expertise, the strong respiratory, inflammation and asthma development expertise of MedImmune (AstraZeneca’s biologics division), AstraZeneca’s global commercial reach in respiratory and gastrointestinal diseases, and the shared resources of two experienced R&D organizations

Under the terms of the agreement, AstraZeneca paid Amgen a $50MM upfront payment and the companies shared development costs. The breakout was as follows: AstraZeneca was responsible for approximately 65 percent of costs for the 2012-2014 period, and the companies now split costs equally. Amgen was to book sales globally and retain a low single-digit royalty for brodalumab. Amgen retained a mid single-digit royalty for the rest of the portfolio with remaining profits to be shared equally between the partners.

It gets even more complicated. Amgen was to lead the development and commercialization of brodalumab (and AMG 557, see below). Amgen was to assume promotion responsibility for brodalumab in dermatology indications in North America, and in rheumatology in North America and Europe. AstraZeneca was to assume promotion responsibility in respiratory and dermatology indications ex-North America. AstraZeneca remains responsible for leading the development and commercialization of AMG 139, AMG 157 and AMG 181. We’ll touch on these other antibodies at the very end.

Back to brodalumab. On balance, Amgen was on the hook for the development and commercialization costs, direct, indirect and ongoing, for dermatology indications in the US and also rheumatology, which in this case refers to psoriatic arthritis and axial spondyloarthritis. On the other hand, AstraZeneca was on the hook for commercialization in respiratory indications worldwide, and dermatology ex-US. This is interesting because brodalumab failed in its’ respiratory indication, moderate to severe asthma, and failed late, in a Phase 2b patient subset trial. So, on balance, much of the overall development cost seems to have shifted back onto Amgen over time (this is not to say that the companies would not have changed terms mid-term, they may have).

Two weeks ago I chaired a session on “Biologics for Autoimmune Disease” at the PEGS conference on Boston. In my opening remarks I used psoriasis as an example of an indication in which we were making clear and important progress, including with IL-17-directed therapeutics. Indeed, psoriasis is now a “crowded” indication commercially, with antibodies and receptor fusion proteins targeting the TNFs, IL-6, IL-12, IL-17, and IL-23 pathways all showing at least some activity. Notably, IL-17 and IL-23 targeting drugs appear to offer the greatest benefit in clearing psoriatic plaques. These pathways intersect in myriad ways, not all of which are well understood. This cartoon shows the effector cytokines and the receptors are expressed by diverse cell types, including dendritic cells, macrophages, T cells, and keratinocytes in the dermis.

IL-17 and friends

In simplistic terms, IL-6 triggers IL-12 and IL-23, and IL-23 triggers IL-17. As mentioned, the IL-17 and IL-23 targeting agents have great efficacy in psoriasis. Amgen and AstraZeneca were preparing an NDA (new drug application) for FDA submission based on results from three large Phase 3 studies. Here are the listed Phase 3 programs for brodalumab:

broda 1

I suppose those Phase 3 studies in psoriatic arthritis will now be tabled or transferred to AstraZeneca. For the sake of completeness here are the earlier studies:

broda 2

Certainly the clinical program was a robust one. So, what went wrong? Amgen R&D head Sean Harper summed up Amgen’s thinking about the suicide issue in the press release: “During our preparation process for regulatory submissions, we came to believe that labeling requirements likely would limit the appropriate patient population for brodalumab.”

The news aggregator and commentary website UpdatesPlus had this to add, questioning whether this result was “bad luck, bad target or victim of brodalumab’s efficacy: Despite high efficacy in Phase 3 studies, whispers of suicidality associated with brodalumab started to emerge at AAD.  At the time Amgen suggested this was related to disease however the company refused to comment on total rates and whether events were seen across arms … The question is whether Amgen is being hyper-cautious or whether the risk of suicidality is especially concerning.  Questions also emerge around the cause of risk – is this a spurious cluster of events unrelated to brodalumab; is suicidality perhaps related to relapse from the excellent efficacy associated with brodalumab after withdrawal (remember most patients exhibited at least PASI 90 on treatment but durability was very poor upon withdrawal); or perhaps suicidality is related to blocking the IL-17RA (note that suicidality has not to our knowledge been reported for the IL-17A ligand mAb Cosentyx) … One final point is whether regulators will now reevaluate suicide risk of IL-17 related molecules as a class – much greater clarity of brodalumab data is required to make a judgement.” That’s quite a nice summary from UpdatesPlus.

FierceBiotech’s report added “AstraZeneca would face some stiff competition if it decides to move forward solo on the drug. Novartis is already well in front with its IL-17 program for secukinumab, approved in January as Cosentyx. Eli Lilly has also been racking up positive late-stage studies for its IL-17-blocking ixekizumab, trailed by Merck’s MK-3222 and Johnson & Johnson’s IL-23 inhibitor guselkumab.”

Still, brodalumab demonstrated remarkable efficacy in psoriasis – Amgen and AstraZeneca went so for as to include a PASI100 score in one of their trials, meaning 100% clearance of psoriatic plaques, and the drug would have shown well against the best of breed, which today is likely Novartis’ anti-IL-17 antibody secukinumab. It is crowded space however, with antagonists targeting multiple nodes in the IL-17/IL-23 axis, alongside the biologics mentioned earlier.

Here is the current landscape from CiteLine (including brodalumab):

CiteLine

All in all, a tough crowd, and one that Amgen likely felt it could not face with a compromised label.

Let’s go back to the question posed above: bad luck, bad target or victim of superior efficacy? “Bad luck” suggests a statistical fluke in the data, potentially caused by the generally higher rates of suicidal tendencies observed in the moderate to severe psoriasis patient population. “Victim of superior efficacy” is in a sense a related issue, since the suggestion is that the loss of responsiveness to the drug, or a relapse, triggers a suicidal response as plaques return. Neither of these statements is really formulated as a hypothesis, and it doesn’t matter, as we don’t have the actual trial data yet with which to perform hypothesis testing.

“Bad target” is the most worrisome suggestion, and this can be formulated as a hypothesis, formally, the null hypothesis is that targeting the IL-17 receptor does not cause suicidal tendencies. Unfortunately, we still can’t test the hypothesis, and it seems likely that having the actual data won’t really help, that is, the study is probably not powered to reject that particular null hypothesis. So, what do we know? A few things, as it turns out.

First is that a link between the immune system and the nervous system is well established, although much of the focus has been on the role of neuronal enervation on immune responses. But clinically at least, the picture is muddier than that. High dose IL-2 can cause neurotoxicity, even hallucinations, according to Dr. Kathleen Mahoney, an oncologist at Beth Israel Deaconess and the Dana Farber. But what is really interesting is what else happens: “Some IL-2 treated patients can have odd dreams, really crazy dreams, and they last for weeks after treatment, long past the time when IL-2 would still be present in the body”, Dr. Mahoney said. Interferon alpha therapy is associated with pathological (severe) fatigue and also depressive symptoms that develop after 4–8 weeks of treatment. Of note, preventive treatment with anti-depressants, in particular serotonin reuptake inhibition attenuates IFN-alpha-associated symptoms of depression, anxiety, and neurotoxicity. Some researchers have suggested (controversially) that anti-TNF antibodies can control depression. Such anecdotal clinical observations suggest that we really do not yet understand the immune system connection to CNS activity.

On the other hand, antagonism of cytokine activity, and particularly of the cytokines IL-6, IL-17 and IL-23, has not been associated with neurological symptoms. For example the anti-IL-6 receptor antibody tocilizumab has shown a positive impact in rheumatoid arthritis patients quality of life scoring, which includes fatigue, anxiety, depression and a number of other factors. More to the point, the anti-IL-17 antibody secukinumab, that targets the IL-17 ligand (rather than the receptor), has not shown a link to suicide.

Clearly more data are needed, and it would not be surprising if the FDA began a drug class review if the data in the brodalumab trials warrant. They could cast quite a wide net given the complexity of this pathway, which overlaps with IL-6, IL-12 and IL-23. This casts a pall over the dermatology and particularly the rheumatology landscape, which is really waiting for novel therapeutics to move them successfully into new and important indications such as lupus and Type-1 Diabetes. The IL-17/IL-23 axis was to be that next great hope, and with luck we will still see these drugs moving out of their core indications of psoriasis and inflammatory bowel disease into new indications.

One last thing.

Those other antibodies – where are they now? A quick scorecard:

snapshot

It is readily seen that none of these are beyond early Phase 2, so it’s fair to say that the rest of the Amgen/AstraZeneca partnership has a long way to go. I, for one, wish the ongoing collaboration the very best of luck, particularly in the lupus indications, where we can really use some good news.

stay tuned.

Holiday Reading

some of the stuff we’re reviewing over the holiday break. N.b. paywalls ahead!  And at the very end, some current non-science favorites.

Tumor Mutational Landscape

Age related variants of variants occurred in three genes (DNMT3A, TET2, and ASXL1) are associated with hematological malignancy risk  http://www.nejm.org/doi/full/10.1056/NEJMoa1408617 and  http://www.nejm.org/doi/full/10.1056/NEJMoa1409405

News and Views on the NEJM papers  http://www.nature.com/nrg/journal/vaop/ncurrent/full/nrg3889.html

using siRNA to identify driver genes in breast cancer  http://www.nature.com/nrg/journal/v16/n1/full/nrg3875.html

Immunotherapy

a primer on the role of PD-1 pathway inhibitors in Hodgkin’s Lymphoma, from Nat Rev Clin Oncol  http://www.nature.com/nrclinonc/journal/vaop/ncurrent/full/nrclinonc.2014.227.html

the role of TILs and TIL-associated TNF in the survival of CRC patients  http://www.jci.org/articles/view/74894

nivolumab in metastatic RCC, published data  http://jco.ascopubs.org/content/early/2014/12/22/JCO.2014.59.0703.abstract

resistance to T cells in melanoma (hint: they lose MHC expression)  http://clincancerres.aacrjournals.org/content/20/24/6593.abstract

interesting look at PD-L1 expression of the response of RCC to targeted therapies  http://clincancerres.aacrjournals.org/content/early/2014/12/23/1078-0432.CCR-14-1993.abstract

it’s hard to control ipilimumab-induced tox  http://clincancerres.aacrjournals.org/content/early/2014/12/23/1078-0432.CCR-14 2353.abstract

IO combination review  http://clincancerres.aacrjournals.org/content/20/24/6258.abstract

tumor/microenvironment cross-talk mediated by microRNAs  http://clincancerres.aacrjournals.org/content/20/24/6247.abstract

functional blockade of miR-23a releases TILs in an ex vivo NSCLC assay  http://www.jci.org/articles/view/69094

neutrophils, T cells and lung cancer  http://www.jci.org/articles/view/77053

Given the new immunotherapy data in bladder cancer, a review of the molecular drivers of this tumor type is most welcome  http://www.nature.com/nrc/journal/v15/n1/abs/nrc3817.html

MDSC requirements for survival  http://www.cell.com/immunity/abstract/S1074-7613(14)00436-1

Gene Therapy and CAR T

Novel gene therapy methods puts a safety brake on a retrovirus-based vector  http://www.nature.com/nrd/journal/v13/n12/full/nrd4495.html

a new review of the CRISPR, Talen, and ZFN technologies for gene editing  http://www.jci.org/articles/view/72992

NY-ESO-1 CAR T P1 results in solid tumors: long term follow-up and correlates of response  http://clincancerres.aacrjournals.org/content/early/2014/12/23/1078-0432.CCR-14-2708.abstract

Targeted Therapies

A very timely primer of the role of different PI3K isoforms in diverse cancers  http://www.nature.com/nrc/journal/v15/n1/abs/nrc3860.html

a Notch in the cancer treatment belt? Nope, a bit of a toxic mess made with anti-DLL4 antibody Demcizumab from OncoMed  http://clincancerres.aacrjournals.org/content/20/24/6295.abstract

IL-17 and colon cancer?  http://www.cell.com/immunity/abstract/S1074-7613(14)00446-4

Hematological Malignancies

von Adrian and Sharpe tease apart Follicular Lymphoma  http://www.jci.org/articles/view/76861

the role of one of gp130 in multiple myeloma  http://www.jci.org/articles/view/69094

Fibrosis, Inflammation, Metabolism, MS

a brand new fibrosis review  http://www.jci.org/articles/view/74368

the TRPV4 pathway, TGFbeta and IPF  http://www.jci.org/articles/view/75331

The role of novel branched fatty acid esters of hydroxy fatty acids in Type 2 diabetes  http://www.nature.com/nrd/journal/v13/n12/full/nrd4501.html

will STING finally yield a useful target in lupus?  http://www.jci.org/articles/view/79100

an animal model of JCV infection and PML  http://www.jci.org/articles/view/79186

Investment and Deals

Pharma funding to pull programs out of the academic space  http://www.nature.com/nrd/journal/vaop/ncurrent/full/nrd3078-c2.html

some color from NRDD on the Genentech + NewLink IDO-1 inhibitor deal  http://www.nature.com/nrd/journal/v13/n12/full/nrd4502.html

Also notable

300,000,000. A violent graphic lurid hypnotic novel of the dissolution of consciousness and the consequence of multiple realities converging within our unprepared empty minds and upon our decadent culture. Horrific and wonderful, but not for the squeamish.

Thug Kitchen – eat like you give a #$%@^. Fun, but you get the idea.

Death & Co: Modern Classic Cocktails. Drink like an adult.

Inflammation, autoimmunity & oncology drug development questions for 2014: Lupus

Lupus and lupus nephritis update

The title includes the word “update” but that may be a bit generous. A dive into the American College of Rheumatology (ACR) abstracts shows that there is not much to update (http://acrannualmeeting.org/). Progress with new therapeutics remains slow.

Most patients are treated with various combinations of cytotoxic agents and immunosuppressants. These include prednisolone, mycophenolate mofetil, tacrolimus, cyclophosphamide, and azathioprine among others. Unlike the situation in RA, we do not have a new suite of drugs for systemic lupus erythrmatosis (SLE) and lupus nephritis (LN) patients.

Newer therapies can be grouped into 2 classes. The most effective class includes the B-cell depleting antibodies rituximab (anti-CD20, aka Rituxan) and epratuzumab (anti-CD22). Clinical trials report consistent and durable improvement in patient symptoms and perhaps even rate of flares. In 2012 the ACR included Rituxan use in its treatment guidelines for patients with advanced diseases (grades III-IV). Rituxan in combination with cyclophosphamide or other standard of care is currently in clinical trials for use in SLE and LN. Epratuzumab is being developed by UCB and Immunomedics and is currently in phase 3 for SLE, with data due in 2015. Certainly the available clinical data indicate that this drug will find use in the treatment of lupus.

The second class consists of the BAFF/Blys and April antagonists. Belimumab (brand name Benlysta), developed by HGS and then acquired by GSK, is an antibody to Blys, a B cell growth and survival factor. Belimumab continues to report long term benefit for patients with generally mild to moderate SLE. There is consistently improvement in patient symptoms by the SLEDAI and BILAG outcome scores, reduction in proteinuria, and in some cases a reduction in the dose of steroids required to control diseases flares. Blisibimod, a peptibody inhibitor of Blys, had updated results from SLE trials, showing reduced proteinuria and Ig levels from the PEARL-SC trial. However, outcome data from that trial was lacking. This drug from Anthera has had a mixed track record in terms of efficacy and so the jury will remain out until the phase 3 data are reported. Other drugs in the space have failed outright, including atacicept, a TACI receptor fusion protein that antagonizes both Blys and April. Toxicity associated with this drug, and lack of efficacy, halted development.

Following the outright failure of the Interferon alpha antagonists a year or more ago, new drugs are few and far between. One of these reported at ACR is AMG811, an anti-interferon gamma antibody from Amgen. This drug appears to have significant adverse event issues, and no sign of efficacy in an early clinical trial. However Amgen is still recruiting for phase 2 trials in cutaneous lupus and SLE with renal involvement. Another Amgen drug, AMG557, is an anti-B7RP-1 (aka ICOSL) antibody which will be interesting to track.

Again, this is an underserved area in terms of new and effective drug development, and it may be we have to rely of the B cell inhibitors and Bly inhibitors for the foreseeable future. Following the failure of many therapeutics over the past few years, we appear to be in a slow period for clinical development. The question we can ask for 2014 and beyond is pretty simple: what will be the new therapeutic hypotheses for lupus and lupus nephritis?