Category Archives: Amgen

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):


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:


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.

Hematological Malignancies – who will win the battle for patients? Part 2: BiTEs & CARTs targeting CD19

 We talked last time about the potential of Macrogenic’s DART bi-specific technology and we focused primarily on the T cell engaging bi-specifics, such as DART006, a CD3 x CD123 therapeutic. Lets just quickly state the hypothesis:

Bi-specific modalities will allow the targeting of the patients T-cell driven immune       system to a precise (tumor-expressed) antigen.

Other outcomes are possible. For example, the drugs might not work at all, or they might not be as specific as designed, or they act in ways we have not anticipated. In the context of the Macrogenics platform, we actually don’t know yet, as DART006 is very early in clinical development. BiTEs (Bi-specific T cell Engagers), Micromet’s version of a bi-specific technology, have been around a while and are further advanced. Acute Lymphocytic Leukemia (ALL) patients are now being recruited into Phase 3 clinical trials for blinatumomab, the anti-CD3 x anti-CD19 BiTE, with study completion due in July 2017. Micromet was acquired for 1.2BB dollars in January 2012 by Amgen. At the time Amgen R&D head Roger Perlmutter pointed to the Phase 2 clinical trial results in ALL as driving Amgen’s interest in the technology. Indeed, blinatumomab has produced some remarkable data in ALL. Historically, chemotherapy treated ALL patients had a complete response rate (CR) of about 38% and a median overall survival (OS) of 5 months. Rituximab (anti-CD20) didn’t perform much better than chemo. In the blinatumomab Phase 2 trial of adult relapsed/refractory (r/r) ALL, patients received a continuous IV infusion of blinatumomab for 28 days followed by 14-days off drug. Patients who responded could re-up for 3 more cycles of treatment or proceed to allogeneic stem cell transplantation (HCST). There was a very high rate CR of ~70% and the apparent absence of minimal residual disease (MRD) in many patients. Blinatumomab also impacted overall survival (OS) in ALL, as reported at the American Society of Hematology conference (ASH) in 2012 (Abstract #670). The CR was still 69% with most patients being MRD negative. The OS for responders was 14.1 months while the OS for non-responders was 6.6 months (so median OS = 9.8 months). Thirteen of the 36 patients enrolled were able to receive allogeneic HSCT.

The most common adverse events (AEs) were fever, headaches, tremors, and fatigue. Some patients experienced severe AEs (SAEs) such as cytokine release syndrome (CRS) and central nervous system events, including seizures and encephalopathy. One patient stopped treatment due to fungal infection leading to death. So, there is tox to consider.

A smaller study directed to salvaging patients with MRD despite prior treatments showed even more dramatic results: 16/21 patients became MRD negative and the probability for relapse-free survival was 78% at a median follow-up of 405 days. This is a remarkable result. An SAE led to one drug discontinuation.

Last year at ASH (Abstract #1811) we saw early results from an open label phase 2 study in r/r Non-Hodgkin’s Lymphoma (NHL), specifically, Diffuse Large B cell Lymphoma (DLBCL). Blinatumomab was administered by continuous IV for 8 weeks. Patients received either stepwise blinatumomab dosing of 9, 28, and 112 μg/d during weeks 1, 2, and thereafter, or received 112 μg/d throughout. All patients received prophylactic dexamethasone. So you can see some dose modifications here designed to reduce SAEs. After a 4-weeks off drug, patients who had responded could receive a 4-week consolidation cycle. 11 patients had been enrolled, 7 patients were evaluable for response. These patients had failed >2 prior therapies, including some patients who had relapsed after HSCT. The overall response rate (ORR) was 57% (14% CR plus 43% partial response (PR); 30% had progressive disease (all from the stepwise dose regimen). Note this is a very small sample size so every patient has a large impact on the response numbers. Ten of 11 patients had at least one grade ≥3 AE with 2 patients having grade 4 AEs (one patient with neutropenia and leucopenia; one with respiratory insufficiency). There were no drug related fatalities. Ten of 11 patients had central nervous system (CNS) AEs, mostly tremor, speech disorder and disorientation: in 5 patients these CNS toxicities were grade 3. The overall benefit/risk assessment suggested stepwise dosing (9, 28, 112 μg/d) to be the recommended dose.

Well first of all let’s point out here that blinatumomab has orphan drug status for ALL and NHL. That’s just to remind ourselves that these are pretty rare diseases with high unmet need. For ALL in particular this seems a good risk/benefit scenario. Within the diseases that make up NHL, DLBCL is not the most treatable (nor the least), and we note also that there is no attempt in the open-label phase 2 to characterize DLBCL into its subclasses – these have different oncogenic drivers and different outcomes for patients. Blinatumomab has also been in Phase in in other NHL classes, including Mantle Cell Lymphoma and Follicular lymphoma. Response rates were generally below current standard of care. Similarly, we can go back to look at rituximab, ofatumumab, and even ibrutinib, idelalisib and ABT-199 in NHL and likely find better treatment paradigms for r/rDLBCL than this, although maybe not as a monotherapy (see those earlier posts here:

Given the modality (CD3 x CD19 bi-specific) maybe the most interesting comparison is with Novartis’ CAR-T CD19 technology CTL019. CTL019 is the product of genetic engineering technology developed by Carl June’s group at U Penn, and is currently advancing in close to 20 clinical trials. The most advanced is a Phase 2 trial in r/r ALL, with a primary outcome completion due in July of 2015. As a quick reminder, CARs combine a single chain variable fragment (scFv) of an antibody (e.g. anti-CD19) with intracellular signaling domains from CD3 and 4-1BB into a single genetically engineered chimeric protein. The CD19-specific version of this technology is termed CTL019. Patient’s T cells are lentivirally transduced with a CAR, expanded ex vivo then infused back into the patient. Infusion of these cells results in 100 to 100,000x in vivo T cell proliferation, anti-tumor activity, and prolonged persistence in patients carrying CD19+ B cell tumors. Results from a pilot study in pediatric and adult r/r ALL were presented at ASH in 2013 (Abstract #67). Most patients received lymphocyte-depleting chemotherapy just a few days prior to infusion. This helps de-bulk the malignancy. In this small trial, 82% achieved a CR, 18% did not respond. Of the patients achieving CR, 20% subsequently relapsed. The rest of the patients are being followed and there has been no update. Responding patients all developed CRS, and about 30% of patients were treated with the IL6-receptor antagonist tocilizumab plus corticosteroids to control CRS symptoms.

We have a little more data on CTL019 from NHL studies, specifically r/r CLL. In December 2013, Phase 2 data were presented at ASH (Abstract #873).  Patients with r/r CLL received lymphocyte depleting chemotherapy and then one of several doses of transduced T cells (this is a dose study in that regard, although, cutting to the chase, no dose response was seen, so lets skip over that). Median follow-up for analysis was 3 months at which time the ORR = 40% (20% CR plus 20% PR, with clearance of CLL from the blood and bone marrow and at least a 50% reduction in lymphadenopathy. The toxicity profile was similar to that described above, dominated by treatable CRS. In a small Phase 1 study (Abstract #168), adult patients with r/r NHL including patients with chemotherapy-refractory primary mediastinal B cell lymphoma and DLBCL were enrolled. They received chemo to reduce disease burden and then an infusion of CTL019. 12 of 13 evaluable patients responded (ORR = 93%), the CR = 54% and PR = 38%. These are outstanding responses.

So let’s take a step back. It is a bit hard to compare these regimens head-to-head as they are in different stages of clinical development, the trails are generally small, and in the case of NHL, we have limited data on different types of lymphomas. At the same time we have to consider the larger landscape of therapies available, and ask ourselves how patients will best be served. In the case of the T cell engaging bispecific antibody landscape, it is very clear that robust anti-tumor responses are generated with very low concentrations of antibody. It seems to me very likely that there will be malignancies or subsets of malignancies where this technology will be very useful, including ALL, as we just saw. It will be important to either improve the antibody construction or alter the dose regimen sufficiently to reduce the toxicities associated with the BiTE therapeutic and competing modalities, including the DARTs. Now, people will claim that the tox is not so bad, and that it is only efficacy that matters, and that’s fine, but in the face of competition from CTL019 and other therapeutics, maybe this becomes a differentiating issue. This might also be different for the pediatric population (a critically important population in ALL) versus the adult population. When we look at the CAR T cell transduction technologies we need longer follow-up on the phase 2 studies but certainly anecdotal evidence from smaller trials suggests that some patients will experience long-lasting remissions. If this observational information holds up in the larger clinical trials than the technology will cement itself a place in ALL therapy, and perhaps in other diseases as well. We don’t know yet whether the BiTE therapeutic blinatumomab or the CAR therapeutic CTL019 will have a top-tier profile in NHL. This may change as more data become available, as some of the small studies are very encouraging. One of the interesting twists to the CAR technology is the question of how to make it widely available. In host-institutions (The U Penn system, MD Anderson, NCI) this is a centralized procedure, and in medical institutions world-wide, core patient cell facilities are commonplace. However it is rumored that Novartis at least wants to maintain the core facility model, as they picked up the Dendreon facility in Morris Plains New Jersey (at a bargain price) specifically to support CAR technology, and plan to duplicate those capabilities in Basel and in Singapore. Perhaps yesterday’s pickup of Israel’s Gamida Cell also plays into this centralized cell handling model. None of these complexities will bother the bi-specific therapeutics as these are injectable – that said, I’m not sure anyone will choose walking around with an IV pump for two months if they can avoid it.

So while these therapies and those like them are very potent, we will have to see how patients and providers ultimately use them.

Now, we’ve unfairly used blinatumomab and CTL019 to illustrate what are both pretty large areas of therapeutic development. We’ll come back to talk about the other players in the bispecific antibody and CAR spaces very soon.

stay tuned.

AML Therapeutics Part 3: Immunotherapy

Ryan Teague and Justine Kline recently put together a nice review of immune evasion in acute myeloid leukemia (AML). The open access paper is available online ( These authors have particular interest in tumor escape from immune surveillance by two interesting mechanisms. The first is termed T cell exhaustion, and refers to a non-responsive state induced in CD8+ (cytotoxic) T cells. The second is immune suppression, mediated by TGFbeta and regulatory T cells (Tregs). Other means used by tumor cells to avoid the immune system include deactivation by co-opting signals that directly shut down immune responses, such as PD-1 and other signaling mechanisms.

Why the interest in immunotherapy for such an aggressive cancer? There are a number of good reasons. First I think it is fair to state that targeted therapeutics (small molecule drugs) and antibodies (mAbs, ADCs, bispecifics) have yet to achieve a breakthrough in AML. The best of these drugs, even in combination, are only modestly effective. The second reason, implicitly recognized by the T cell engaging bispecific antibodies (BiTEs, DARTs) and by the still nascent CAR-T cell engineering technology, is that there is evidence to suggest that AML can be controlled by an effective immune response. This evidence comes from the leukemia transplantation field. As Teague and Kline state:

“Treatment with modern chemotherapy regimens often induces complete remission, but a majority of patients will ultimately relapse … it has been recognized that allogeneic stem cell transplantation can be curative for some patients with AML … derived from the so-called graft-versus-leukemia effect thought to result … Unfortunately, only a minority of patients with AML are candidates for this procedure.”

Those who are familiar with allogeneic SCT will further recognize that this is a risky procedure that can outright fail. So, are there safer or more direct ways to harness an anti-tumor immune response?

Novel therapeutics developed to stimulate anti-tumor immunity include the CTLA4 antagonist mAb, ipilimumab (Vervoytm; Bristol Myers Squibb (BMS)), approved for use in refractory or non-resectable melanoma. BMS is also developing the anti-PD1 mAb nivolumab, and combination trials with ipilimumab are underway. Other anti-PD1 and anti-PDL1 antibodies in advanced development for a variety of tumor types include MK-3475, submitted last month for FDA approval for the treatment of advanced melanoma, MPDL3280A (Roche), MEDI4736 (Astra Zeneca), and others. These are critically important therapeutics in hematological cancer and solid tumors. The potential breadth of applications is illustrated by the announcement last week the Merck will seek collaborative partnerships to develop MK-3475 in combination therapies. Merck will partner with Pfizer to investigate combination therapy in a phase 2 renal cell carcinoma (RCC) trial with the VEGFR inhibitor axitinib (Inlytatm). Merck will also partner with Pfizer for a phase 1 trial(s) using MK-3475 with the agonist anti-41BB antibody PF-2566, in multiple cancers. Readers will note that 41BB signaling is a critical component of the CAR-T T cell engineering technology. The collaboration with Incyte is also a dual-immunotherapy approach, as MK-3475 will be combined with INCB24360, an IDO inhibitor, in a phase 1 non-small cell lung cancer (NSCLC) trial. IDO is secreted by tumor cells, is a mediator of T regulatory T cell activity, and in AML is associated with poor prognosis. With Amgen, MK-3475 will be used in combination with the oncolytic viral therapeutic T-VEC, which induces tumor cell death and stimulates anti-tumor immunity.

The point of all this is to illustrate that for difficult cancers – melanoma, RCC, NSCLC – its not going to be easy, and combinations of novel therapeutics will have to be utilized. AML is a very difficult cancer. With this in mind we can look at the state of immunotherapy drug development in AML.

The Teague and Klein review goes into considerable detail on this subject, so we’ll just hit a few highlights and then see if we can update the storyline. A point the review makes that I didn’t fully appreciate is that AML tumor cells (and many others) can downregulate MHC Class I and II, making the tumor cells difficult for the immune system to recognize in the context of allogeneic SCT. This fundamental type of immune evasion may be difficult to circumvent. Other mechanisms of immune evasion used by AML include expression of PD-1L on the tumor cells, which effectively shuts down tumor infiltrating T cells that express PD-1, the PD-L1 receptor and mediator of a potent signaling response that downregulates T cell activity. AML tumor cells also express B7 family proteins B7-1 and B7-2,that bind to CTLA4, another downregulatory receptor. Clinical trials enrolling AML patients for treatment with therapeutics such as ipilimumab, nivolumab etc are described in the review. Its sufficient to point out that the effort to use these therapeutics for AML is in its very earliest stages.

A few recent observations point to other immune evasion strategies that night be productively targeted in AML.

Several preclinical studies have identified co-expression of TIM-3 and PD-1 as markers of CD8+ T cell “exhaustion”, and have likewise identified PD-L1 and galectin-9 (a putative TIM-3 ligand) on AML patient cells. TIM-3 is yet another receptor on T cells that mediates downregulation of T cell activity. Other markers of AML cells from patients were recently described (

Relevant proteins included B7-2 (CD86), B7-H3 (CD276) and PD-L1. Patients with very high expression of both B7-2 and PD-L1 had worse overall and relapse free survival. HVEM, a receptor for several critical immune proteins including LIGHT, CD160, and BTLA, was expressed on a subtype of AML with relatively good prognosis. The author’s conclude ” that the profile of immune checkpoint molecules … correlates with molecular disease characteristics in AML and may even possess prognostic information, especially for relapse … (and) as therapeutic targets with respect to boosting anti-leukemic immune responses.”

An example of such an approach is provided by Innate Pharma, which is developing an anti-KIR antibody, lirilumab. KIR negatively regulates NK cell anti-tumor activity. A phase 1 trial in AML is continuing                             ( Preclinical data support the use of this mAb in combination with the cytotoxic anti-CD20 mAb rituximab in lymphoma. One might envision a similar approach using a cytotoxic mAb targeting AML such as the anti-CD33 mAbs discussed in part 2. Another possibility are the anti-CD38 mAbs. Second generation CD38 mAbs with improved cytotoxic activity are under intensive development for multiple myeloma by Sanofi (mAb SAR650984), Jannsen (daratumumab aka HuMax CD38) and MorphoSys (mAb MOR03087).

Another example is CoStim Pharma, bought today by Novartis. In their portfolio are novel immunotherapeutic mAbs, including TIM-3 antagonist mAbs. Novartis is moving quickly here to beef up its immunotherapeutic pipeline, which it can now develop in parallel with the U Penn CAR-T technology. Another local, private immunotherapy company is Jounce Therapeutics.

As we have also seen in parts 1 and 2, drug development for AML lags significantly behind other leukemias, lymphomas, myelomas, and the like. However, targeted therapeutics such as the tyrosine kinase inhibitor sorafenib, HDAC inhibitors vorinostat and panobinostat, and proteosome inhibitors bortezomib and carfilzomib hold some promise. The FLT3 and c-Kit targeting agents seem less likely to provide meaningful long-term benefit, although we’ll see what the combo trials brings. While it is too early to assess the CAR-T technology, the bispecific modalities, or immunotherapies in AML, the cytotoxic mAbs and ADCs should have a prominent role in controlling this aggressive disease.

We asked in Part 1 who the winners would be in 5 years. Looking over the landscape of therapeutics its pretty clear that winning will require collaboration among companies. With that said those companies with the biggest concentration of effort in AML include Merck, Onyx, Novartis, Amgen and perhaps Seattle Genetics. Given their past successes we can be hopeful that several of these companies will succeed in establishing breakthrough treatments for AML. In the end, patients should benefit the most from all of this activity. Perhaps stockholders will also benefit. With this in mind we note that Onyx probably has the most to gain (or lose) in this indication.

 stay tuned.

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 ( 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?