Category Archives: rituximab

Biogen Idec, multiple sclerosis, and the anti-Lingo story

It’s AAN conference week, and we were looking around, trying to get caught up on multiple sclerosis after a few months dedicated to oncology. We stumbled across this analyst report, and just had to comment.

Credit Suisse (CS) recently released a deep-dive report on Biogen Idec’s (Nasdaq: BIIB) anti-Lingo antibody program, assigning between $5-10BB (billion) USD of the total relapsing/remitting Multiple Sclerosis (rrMS) market share to the program by 2020. The program is currently in Phase 2. This analysis, in part, supports CS’s current price target for BIIB stock at $400, leveraging presumed growth due to the view on continued success of the anti-Lingo program. In other words, positive news on this program will help support inflated multiples through 2018, when pivotal trials may actually read out. The analysis seems ill considered, misses key aspects of BIIB corporate strategy, and places undo pressure on an early Phase 2 program. Further, intense focus on the anti-Lingo antibody program in turn places pressure on two early phase clinical trials, one due to read out in 2H14. The implication is that the base case for the price target could be undermined if the very early clinical development of the anti-Lingo program falters. That’s an unfair burden for a single high-risk program to bear.

Let’s dive in. Our focus will be on the science, but we’ll first set the stage. Our driving goal when looking at any biotech company or program is to bet the science, not the hype.

Two years ago the company set an internal goal of “400 in 5″, essentially promising to drive EPS in support of a sustained stock price of $400 USD by 2017. They came close during the biotech bubble that burst earlier this year. The stock is holding its’ own at around $320 USD. The “400 in 5″ goal is in place irrespective of the success or failure of the anti-Lingo program, which cannot read out pivotal clinical trials until at least mid-2018. With that in mind we can deconstruct the CS analysis, and create our own. Importantly, our analysis drastically de-risks the impact of the anti-Lingo program on the trajectory of BIIB growth, while leaving room for very attractive upside if this program hits.

The CS analysis correctly estimates that oral MS drugs will take over an increasing % of market share running from 2014 through 2020. No argument there, and BIIB will take the bulk of this market with Tecfidera, per multiple analysts. But CS believes that the “pipeline focus” is on the anti-Lingo antibody program to will help drive the stock price as the program matures. A few comments:

1) Analyst and/or investor focus on the anti-Lingo program is a sign of pipeline weakness, not strength. Where, one might ask, is the rest of the pipeline?

2) The program is very high-risk (and thus high return) for multiple reasons beyond the inherent weakness of being in Phase 2.

3) Management recognizes the oversized risk of the program, and will not tether stock performance to this program, instead they will act to de-risk the pipeline and performance.

Let’s look at these points one by one. First, the portfolio and pipeline. We agree that top-line growth will continue to be robust, driven by Tecfidera in the expanding orals segment of the market. We believe that the Daclizumab program is likely to succeed (the data being shown at AAN this week is very good) but it seems likely that this drug will compete for the declining injectable biologics market share with Tysabri. Maybe not, if it is successfully positioned for JC virus antibody positive patients, and can hold off the orals. Ocrelizumab may successfully evolve into the successor for Rituxan, an anti-CD20 antibody pulled from the MS market by Genentech/Roche because of exposure to generics competition. STX-100, an excellent program for fibrosis, is emerging into a rapidly evolving IPF treatment landscape (pirfenidone, nintedanib), and we’ll see if the company can eventually steer this drug into other indications, such as systemic sclerosis. The hemophilia biologics Eloctate and Alprolix are approved and launch-ready, with a consensus view that these will pull in 500MM over the first full year of sales, rising to 1BB by 2018. That’s already baked into the current forecasts.  The rest of the programs are as high risk as the anti-Lingo program, so let’s be conservative and assume half or more of these programs eventually fail. Point #2 is that the anti-Lingo program is high risk and can fail for a variety of reasons. At least three can be articulated. First, the therapeutic hypothesis, that axonal regeneration can be induced by a therapeutic in the setting of MS, has never been demonstrated. So there is an inherent biology risk. Second, the preclinical data package supports the hypothesis that blocking Lingo will improve myelin sheath regeneration and axonal function after insult or injury. However the preclinical package using MS animal models is very weak. Finally, the technical hypothesis, that sufficient quantity of antibody can be delivered across the blood-brain barrier in a robust and reproducible manner, patient to patient, has not been demonstrated. So there is an inherent technical risk. It’s also critical to note that the optic neuritis trial, the first Phase 2 to read out, perhaps addresses the therapeutic hypothesis (we could debate this, but won’t) but simply fails to address the technical hypothesis. Focusing investor attention on a Phase 2 readout in optic neuritis as a surrogate for efficacy in MS is a shell game that will go bad quickly if that Phase 2 trials comes in with negative results.

So we agree with CS that anti-Lingo antibody might work in rrMS, and it might not. We disagree that this program should be the focus of interest in the pipeline. We disagree outright with a few of their more outlandish predictions, including the statement that anti-Lingo “has potential in SPMS” the progressive and untreated form of the disease. There is no support for this statement. And while we agree that anti-Lingo is likely to be used in combination with other BIIB MS drugs, trials supporting such use are a very long way away. There is no basis to evaluate such a statement at this time. Finally, instead of concluding that pipeline focus on the anti-Lingo program is a positive, as CS does, we see this as a sign of a fundamentally weak BIIB pipeline.

Should we be surprised? Let’s consider that BIIB has not successfully developed a novel internal program since Avonex and Amevive, well over 15 years ago (yes there is Peligry, but that’s just pegylated-interferon, still, they did develop it). What else? Rituxan came from Idec. Tysabri came from Elan. Tecfidera came from Fumapharm. Daclizumab came from PDL Biopharma/Abbvie. Ocrelizumab came from Genentech/Roche. Long acting Factors XIII and XI came from Syntonix Pharmaceuticals. STX-100 is a BIIB moelcule but had to leave for 5 years in order to be successfully developed by Stromedix. In the meantime the Immunology Department has produced no drugs since it’s inception in the mid-80s, well over 20 years ago. The oncology experiment (BIIB San Diego) produced no drugs. The BIIB hemophilia group will produce no new drugs (more on this below). The medicinal chemistry effort has produced no drugs (although we think they will). The BIIB neurology research group has produced no drugs outside of the interferon space, although they are getting closer (anti-Lingo, BIIB037). So why is this company even competitive, indeed dominant, in MS?

The answer is simple and compelling. BIIB excels in the development of in-licensed, clinical stage MS programs. Look at what they’ve brought in and then brought to registration: Tysabri is the single best MS drug available (nothing else is even close); Tecfidera is the single best oral MS drug, and again it’s not even close; Daclizumab will present an extraordinary efficacy/safety profile, and so on. Let’s also consider that while BIIB was accumulating and developing these assets, their competition was developing cladribine, alemtuzumab (campath), lemtrada, aubagio and other hideous potions. Even Novartis came razor close to missing with Gilenya, a nicely efficacious drug that has a challenging toxicity history

Perhaps anti-Lingo antibody will join the BIIB parade of success in MS, but company management is not counting on it. When management set a goal of “400 in 5″ in 2012, they meant it, which means they cannot wait for anti-Lingo or any other early Phase 2 program to mature. This is our final point from above, that management will de-risk the pipeline. This means they have 2 choices, and they have been excellent at executing on either or both of these choices:

1) Buy a late clinical stage MS asset/company.

2) Cut costs in order to manage EPS aggressively.

A third possible outcome of course is that they will do both. A very interesting question is: what attractive MS asset/company could BIIB buy? There are some very compelling answers, and maybe we’ll share these, but not today. A less interesting question, because the answer is so obvious, is where to cut. Let’s go back to those hemophilia drugs, brought in on a wave of enthusiasm for the much broader hematology space. What happened? When costs needed to be trimmed a “strategic review” quickly revealed that hematology was not so attractive after all. So the hemophilia R&D group was slashed, and only the clinical programs retained. Note further that those Factor XIII and Factor XI drugs are utlilizing very valuable and expensive bio-manufacturing capacity for the company. What might happen here? BIIB could sell the programs for 10-20x annual sales to Bayer or Novo Nordisk and keep the manufacturing rights for 5 years or more. We’re just guessing, but we also think it’s a very good bet.

The other obvious target is the Immunology group. A possible hint here is that a new department has been formed, carrying the name Remodeling and Repair or something similar. The department is built around the very interesting Phase 2 fibrosis program STX-100, mentioned above. A simple decision would be to move the few Immunology clinical assets (the anti-TWEAK and anti-CD40L antibodies) under this new department, and jettison the Immunology Research efforts. Such a move would mimic what was done in the hematology space, and would further move the company further away from basic Research, which historically has failed to move therapeutics forward, and further toward Development: in-licensing, clinical execution, regulatory execution and bio-manufacturing, the company’s true core competencies.

Will BIIB do any of these things? We have no idea. But we have watched this company for a long time, and if top-line results fail to drive EPS to the goals promised, the company will act decisively to control the bottom line. Personally, we expect to see an acquisition in short order, rather than further cuts. Just to reinforce what we said at the beginning: the proposed corporate strategy fundamentally de-risks the impact on the anti-Lingo program on the company fortunes, leaving intact the potential for a large upside if that program performs well in the clinic.

disclosures: PDR was a senior member of BIIB’s Immunology department for a long time, and retains both positive and negative biases. PDR is also long BIIB stock.

stay tuned

Three high-altitude take aways from AACR14

The American Association for Cancer Research (AACR) 2014 meeting last week was high energy and high impact. We will dive into particular talks and specific pathways and indications in later posts, in the meantime I wanted to mention a few key themes.

1) Immunotherapy Versus The World.  That’s a deliberate overstatement of a subtle shift in emphasis from last year’s big meetings, where combinations of immunotherapy with just about anything else were the hot topic. This year there were several talks which emphasized the futility of chasing oncogenic pathways and all of their resistance mutations, one after the other, as opposed to letting the immune system do the work. However, it seems to me overly optimistic to believe that immune modulation can defeat a high percentage of patient  tumors on its own, as some speakers acknowledged. Combinations remain necessary although we will have to work past some notable failures in combo trials, such as the liver toxicity seen in the ipilimumab + vemurafenib combination phase 1, discussed briefly by Antonio Ribas               (see http://www.nejm.org/doi/full/10.1056/NEJMc1302338).

2) Immunotherapy Versus Itself.  In the ultimate battle of the titans, we see different immunotherapeutic modalities squaring off. This is a theme we’ve touched on before in this space, but the  competition is getting heated. In some indications, the leukemias, lymphomas, perhaps melanoma and some other solid tumors, there is an abundance of therapeutic choices, and the hard question of which therapy best suits which patient will ultimately need to be addressed outside of the context of clinical trial enrollment. Several talks really brought this message home. Roger Perlmutter of Merck (and before that, Amgen) envisions an important role for multiple immune therapies including bi-specific antibodies, chimeric antigen receptors (CARs), and immune checkpoint modulators like Merck’s anti-PD-1 antibody MK-3475.  For B cell lymphoma for example, there is blintumumab (Amgen), a potent bi-specific that redirects T cells to CD19+ tumor cells (and normal B cells), and there is CTL019, a CAR therapeutic which does much the same thing. The therapeutic profiles and toxicity differ, but the general idea is the same. One big difference is that while CTL019 drives T cell expansion and the development of long term anti-tumor memory, the bi-specific does not. Which is better? We don’t know yet. He did not mention that one might do well trying a course of BTK inhibition plus anti-CD20 antibody therapy, perhaps with restricted chemotherapy first e.g ibrutinib plus rituximab and chemo (R-BR or R-F). That choice comes down to efficacy, then toxicity, and eventually cost. Efficacy seems to be a home run with the CAR therapeutics, although these may run into trouble in the area of toxicity and cost calculation. Renier Brentjens discussed the CAR therapies being developed under the Juno Therapeutics umbrella. Acute lymphoid leukemia (ALL) can be treated with CAR 19-28z modified T cells to achieve a >80% complete response rate with >70% of patients showing no minimal residual disease, an outstanding result. However, 30% of treated patients end up in the ICU due to cytokine release syndrome and other toxicity, and recently patients in the ALL trials have died from unanticipated tox causes. Juno stopped 5 trials of their CAR technology last week due to toxicity. Apparently one patient died of cardiovascular complications and another of CNS complications (severe uncontrolled seizures) – it was hard to nail down as Dr Brentjens had gone off his prepared talk for these remarks which were off the cuff, so comment please if you have better info on this. Carl June discussed Dr Brentjens’ presentation, noting that the clinical results were really quite striking, and contrasting the CD28 motif-based CARs with the 4-1BB-based CARs (as designed by Dr June with U Penn and licensed to Novartis). He also stressed that in chronic lymphocytic leukemia (CLL) they have had patients who have failed up to 10 prior therapies, including rituximab and/or ibrutinib, and these patients have responded to CAR treatment. That’s very impressive data. The roadblocks to widespread use of CAR therapy however are large and include the toxicity, the “boutique” nature of the current protocols, the cost. Perhaps, Dr June suggested, CAR will end up as third line therapy, reserved for salvage therapy. I for one hope not.

Also in the immunotherapy space were hot new targets (e.g. CD47, OX40, GITR), advances on the vaccine front, and a few surprises. We’ll update soon.

3) The Medicinal Chemists Have Been Busy.  Not to be drowned out by the Immunotherapy tidal wave, small molecule therapies targeting specific oncogenic pathways continue to be developed and show promise. Most readers will be aware of the high stakes showdown (so billed) between Novartis, Pfizer and Lilly in the field of specific CDK4/6 inhibitors – in addition to bringing forward some really nice phase 2 data (we’ll discuss these another time) this “showdown” also illustrates that current portfolio strategy drives a lot of overlapping effort by different companies. As expected, much of the action is moving downstream in the signaling pathways, so we saw some data on MEK1 inhibitors and ERK1/2 inhibition. There were some new BTK inhibitors, nice advances in the epigenetics space, and some novel PI3K inhibitors. All grist for the mill.

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: http://www.sugarconebiotech.com/?p=16).

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.

Oncology drug development questions for 2014: Combination therapies for B cell lymphoma

Part 1 – Ibrutinib and the development of combination therapies for B cell lymphoma

For physicians, patients, investors etc, major medical conferences are a way to check in on the progress of a company’s drugs in the context of the medical communities response to the data, i.e. the buzz. Negative buzz is generally pretty straightforward, reflecting poor results or unexpected toxicity in a clinical trial. Positive buzz should be (and often isn’t) more nuanced, as positive data, while great to see, need to be placed into the context of evolving clinical practice and the ever-present competition for patients. Results, positive or negative, need to be vetted for robustness: clinical trial stage, sample size, design; endpoint design; therapeutic window (the dose range between efficacy and toxicity); and duration of response.

Last year saw extraordinary advances in the treatment of B cell lymphoma, particularly the Non-Hodgkin Lymphomas (NHL) that include well known cancers like Chronic Lymphocytic Leukemia (CLL), Mantle Cell Lymphoma (MCL), indolent NHL (iNHL) and many others. This advances included small molecule therapeutics that target critical drivers of lymphoma cell proliferation and survival, novel antibodies (“naked”, enhanced, payload carrying), ex vivo modified patient T cells that attack lymphomas upon reinjection, and a variety of other modalities. It was interesting to see that the companies getting the most buzz varied during the year, with different companies “winning” different conferences. Be assured that in this context, winning reflects wins for the stock price! Winning in the medical marketplace is a whole different story.

With the medical marketplace in mind, a reasonable question for 2014 pops up when you step back and look at the breadth of the B cell lymphoma therapeutic landscape.

How will biopharmaceutical companies, physicians, and payers develop and use combinations of these therapies?

Lets think about the possible combinations. The most obvious are those that we are already seeing widely used, such as the combination of a small molecule inhibitor with a tumor-targeting antibody. One example is the combination of ibrutinib, a BTK inhibitor, and rituximab, an anti-CD20 monoclonal antibody. Ibrutinib was approved for treatment of relapsed/treatment refractory (rr) MCL in November 2013 under the brand name Imbruvica, and approval for rrCLL is expected soon (these indications were filed for approval together, in August 2013). Patients with relapsed/refractory small lymphocytic lymphoma (SLL) were included in the CLL arm of the clinical trial.

CLL is a good example of the power of combination therapy. Rituximab monotherapy in rrCLL/SLL produced overall response rates (ORR) in the range of 55% and a complete response rate (CR) of somewhere under 10%, depending on the trial. Note here that ORR and CR refer to assessments of tumor burden at a specific and predetermined time after treatment is initiated. A CR does not indicate a cure but rather is a measure of the degree of efficacy. The ORR and CR measurements are most meaningful when presented in the context of duration of response (DOR) or in the context of progression-free survival (PFS) or overall survival (OS).

Monotherapy of rrCLL/SLL with ibrutinib produced ORRs ranging from 70-80%, with CRs ranging from 0 – 10%. Duration of response was good, and there was a measurable impact on PFS. There are different classes of rrCLL patients, based on cytogenetic status. High risk CLL patients commonly carry a deletion on chromosome 17 (del17p) and/or other abnormalities. Such mutations predict poor prognosis for these patients. Last April, the FDA granted Ibrutinib Breakthrough Therapy Designation for high-risk rrCLL/SLL del17p patients based on achievement of a 50% ORR in these patients when given ibrutinib monotherapy.

Now to the combination of ibrutinib and rituximab (and a chemo agent, bendamustine). As discussed in earlier coverage of the American Society of Hematology Annual Meeting (ASH), linked here, treatment of high-risk CLL patients with the combination therapy produced an ORR of 95%, with 78% maintaining response through 18 months. While only 10% of the responses were designated CR, the long duration of the partial responses (PR) was a dramatic result.

The cost of Rituxan treatment for B cell lymphoma is generally quoted at ~10K/month but billed to insurance at about 5K monthly, so we are somewhere between 60-120K per year per patient in the US. Imbruvica will cost 130K per year per patient in the US. Note here that neither therapy, given alone, is considered curative. We don’t know yet what the durable remission rate will be for the combination therapy, where we define durable remission as no detectable disease (in the blood, lymph nodes, bone marrow) without maintenance therapy. Curative treatment means no disease in a patient who no longer requires drugs.

So it’s fair to say that these combination therapies will be very expensive and may need to be used for a long time. Given the current climate of cost control, especially outside of the US, what are companies doing to anticipate eventual pushback on premium pricing?

Just a quick reminder that Imbruvica (ibrutinib) is a Pharmacyclics/Johnson&Johnson (J&J) product and the Rituxan is a Roche product and further, that Roche has a next generation anti-CD20 antibody, obinutuzumab, recently approved for the treatment of CLL (including as first line treatment), under the brand name Gazyva. This antibody given in combination with a cheap chemotherapy agent, chlorambucil, produced an ORR = 78% and a CR of 28% in the phase 3 trial. This antibody was significantly better than Rituxan (rituximab) plus chlorambucil in the same clinical trial (ORR = 65%, CR = 7%). The trial was done in rrCLL patients including high-risk patients defined as del17p.

Another anti-CD20 antibody, ofatumumab from GSK, has been approved for second-line use in rrCLL. This drug, priced at 120K yearly, ran into reimbursement pressure in Europe and the UK as not showing sufficient benefit to justify the price. This is a hint of price pressures to come.

This is where I think things get really interesting. I spent some quality time on clinicaltrials.gov, trying to understand how companies competing in the B cell lymphoma space are looking ahead, the assumption being that one can do this by looking at the trials planned or underway for the top tier drugs. Many of the oral drugs in advanced development for B cell lymphomas are reviewed here.

Nearly all advanced oral drugs for B cell lymphoma have trials underway or planned with an anti-CD20 antibody. Most of these trials are done with rituximab, probably just reflecting the wide availability of this antibody. Perhaps some companies are sticking with rituximab in the belief that generic biosimilar forms of this antibody will become available in Europe (where it is now off-patent) and in the US (where patent protection expires in 2018), which may make combination therapy more widely available. The rituximab trials are not done in collaboration with Roche, with one notable exception which we will get to later.

There are 11 clinical trials listed as active that include ibrutinib with rituximab either alone or with various other agents. Some of these trials have already read out results:

TRIAL NUMBER
PHASE
DATE FILED
IBRUTINIB WITH
INDICATION
NCT01980654210/24/2013rituximabuntreated FL
NCT0188056726/4/2013rituximabrrMCL
NCT0152051921/25/2012rituximabhigh risk CLL, SCL
NCT0161109035/15/2012rituximab/bendamustinerrCLL, rrSCL
NCT0177684031/24/2013rituximab/bendamustineuntreated MCL
NCT01479842111/1/2011rituximab/bendamustinerr DLBCL,MCL,iNHL
NCT0185575035/14/2013R-CHOPDLBCL-ABC
NCT0188687236/24/2013noneuntreated CLL
rituximab
v rituximab/bendamustine
NCT01974440310/28/2013R-CHOPrr iNHL
v rituximab/bendamustine
NCT0188685916/24/2013lenalidomiderrCLL, rrSCL
NCT0182956814/9/2013lenalidomide & rituximabrrFL
NCT0195549919/27/2013lenalidomide & rituximabrr iNHL

Note that FL is follicular lymphoma and DLBCL is diffuse large B cell lymphoma. DLBCL-ABC is a subtype. These are all types of B cell lymphomas. R-CHOP is rituximab plus a standard mixture of chemotherapeutic agents, and I may or may not have defined this correctly, suffice to say if it says CHOP then there is a potent mix of chemo being given; “v” means versus, that is, it is a comparator arm.

There are another seven or eight single agent ibrutinib trials also, but I did not include those here, so what we see all together is a full court press of clinical trials designed to show benefit of ibrutinib in multiple different B cell lymphomas, as first line or second line therapy. These trials will produce a tidal wave of data that, if positive, will by their sheer volume place ibrutinib at the top of the heap of B cell lymphoma oral agents. So, yes, I’m betting on Pharmacyclics (stock symbol PCYC) and J&J to win the marketplace, at least for the near term.

Ibrutinib development does not stop there. There are three trials with lenalidomide, also known as Revlimid, approved as second line therapy for multiple myeloma (MM). A monotherapy trial of lenalidomide in CLL was halted last year due to an increase in deaths seen in the active arm. Even at a reduced dose (I’m guessing here) the use of this agent plus ibrutinib plus rituximab seems risky. Also, the drug is owned by Celgene. So why conduct trials with lenalidomide at all? The answer to that question will be found in the list of clinical trials for CC-292, Celgene’s BTK inhibitor under development for B cell lymphoma.

But just to finish with ibrutinib. Here are the rest of the active clinical trials I could find:

TRIAL NUMBER
PHASE
DATE FILED
IBRUTINIB WITH
INDICATION
NCT020131281,212/11/2013ublituximabCLL, MCL
NCT0157870734/11/2012v ofatumumabrrCLL
NCT012177491,210/7/2010ofatumumabCLL
NCT01478581211/18/2011nonerrMM
NCT0184172321/24/2013noner Hairy Cell leukemia
NCT019627921,29/27/2013carfilzomibMM

Ublituximab is a new anti-CD20 antibidy from TG Therapeutics and the clinical trial is being run by that company, not by J&J/PCYC. In contrast the ofatumumab trials, which are “active but not recruiting” are sponsored by Pharmacyclics.

Finally, just some tidbits. Ibrutinib presentations recently have included studies in some interesting new indications, particularly MM. There are two MM trials shown here, the second one being run in collaboration with Onyx Pharmaceuticals, whose proteosome inhibitor carfilzomib, has been approved for treatment of rrMM under the name Kyprolis.

I suspect we will see many more such collaborative efforts as the field matures.

Next up we will look at the efforts of two of the compounds seeking to compete with ibrutinib, Gilead’s idelalisib and Celgene’s CC-292.

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 (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?

SnapShots from the 2013 American Society of Hematology Abstracts – Part 5

 
Part 5. Key Biologics in Clinical Trials.
November 20, 2013
The American Society of Hematology Meeting will take place in New Orleans,
December 7 – 10, 2013. The abstracts are available at http://www.hematology.org/Meetings/Annual-Meeting/Abstracts/5810.aspx
In parts 1-4 we meandered through the small molecule, mainly oral drugs,
highlighting a few key pathways and focusing mainly on CLL.
Biologic drugs are a different and equally important class of therapeutics for lymphoma
treatment, and really it is Rituxan, the antibody that depletes cells expressing CD20, that
ushered in the new era of non-chemotherapy-based drugs. Some of the small molecule
trials discussed earlier were done in combination with anti-CD20 antibodies with or
without added chemotherapy. This therapeutic trend toward combination therapy will
dominate the lymphoma landscape, with chemo, targeted small molecules, and antibodies available to mix and match, just so long as they are not too toxic when combined, provide additive efficacy, and we can afford to pay for them. One might also overlay immuno-
therapy approaches – checkpoint modifiers, CAR-T modified cells, even cancer vaccines -
and of course there is also the whole bone marrow or stem cell transplantation field.
There are notable new biologics being developed for the treatment of lymphoma, and a
few of these have new data available in the ASH 2013 abstracts.
The real question is whether anything will be able to compete with the novel anti-CD20
mAb obinutuzumab.
Obinutuzumab (GA101) is aglycoengineered antibody having 10-fold greater affinity 
for FcgammaR3A. This is receptor on cytotoxic NK cells that binds to the Fc domain 
of the antibody. The binding of the Fc domain to the FcR (receptor) triggers killing of 
the target (CD20+) cell by the interacting NK cell. Obinutuzumab was approved under 
the brand name Gazyva on November 1st for use in combination with chlorambucil to 
treat patients with previously untreated CLL. This was this first drug approved under 
the FDA’s new breakthrough therapy designation and wasbased on a Phase 3 study of 
previously untreated CLL patients (n = 365) comparing Obinutuzumab plus chlorambucil 
to chlorambucil alone. The PFS for the combination therapy was 23 months compared 
with 11.1 months with chlorambucil treatment. Additional data from the Phase 3 trials, 
comparing obinutuzumab pluschlorambucil (OB-c) to rituximab (Rituxan) plus 
chlorambucil (R-c), are to be presented during the plenary session at ASH (Abstract #6). 
Those data are summarized as follows:
ORR
CR
MRD*
PFS
OB-c
78%
21%
29.4%
26.7 months
R-c
65%
7%
2.5%
15.2 months
*: MRD is minimal residual disease, meaning that bone marrow and organs are negative 
for tumor cells.
AEs were higher in the obinutuzumab plus chlorambucil arm, although it appears that 
this was due to increased severe infusion-related reactions, which can be controlled.
Another study in previously untreated CLL patients will be presented at ASH (Abstract
#523). In this trial, obinutuzumab (OB) was combined with fludarabine/cyclophosphamide 
(FC) or bendamustine (B). There are 41 patients enrolled and the median reported followup 
time is nearly 12 months. 9 patients (22%) had to discontinue treatment due to AEs, mainly cytopenias. The investigators will report and update response data, summarized here (note 
that CRi, defined as complete response with incomplete bone marrow resolution, is included 
in this table with the %PR):
ORR
CR
PR
SD
PFS
OB-FC
62%
9.5%
47.6%
19%
not reached
OB-B
90%
20%
70%
0
not reached
No responding patients progressed and PFS was not reached. While the data look very good
for efficacy, the fact that a high percentage of patients had to discontinue due to AEs is
notable.
Two other studies will be presented at ASH. One is on the treatment of CD20+ Diffuse
Large B Cell Lymphoma (DLBCL) patients in a Phase 2 clinical trial (Abstract #1820).
DLBCL is an aggressive lymphoma, currently treated with combination chemotherapy
(CHOP: cyclophosphamide, doxorubicin, vincristine, prednisone) or with rituximab plus combination chemotherapy (R-CHOP). In this trial, 80 previously untreated DLBCL
patients were treated with obinutuzumab plus CHOP. The ORR = 83%, consisting of
CR = 55% and PR = 28%. Of the 80 patients total, 11 patients discontinued treatment,
5 of these due to AEs (6.25%), but in general AEs were manageable. Nine patients had
PD, three died. These preliminary results are very encouraging, updated results including
analyses responses in DLBCL subsets (ABC v GC) and with reference to molecular
classification will be presented at the meeting. An earlier study (Abstract #1814) will
present data on the use of obinutuzumab as maintenance therapy after induction therapy
with chemo (either OB-CHOP or OB-FC). Patients had rrFL (follicular lymphoma). The
induction data was published by Radford et al. in Blood, 2013, volume 122, page 1137ff. 
CR rate was monitored at the start and end of maintenance therapy, with the maintenance 
period being a median of 35 months across the two cohorts. CR as a best overall response increased on maintenance with obinutuzumab in the OB-CHOP cohort (52%, PFS not 
reached) and in the OB-FC cohort (82%, median PFS = 46 months). Finally, a combination 
trial of obinutuzumab and ABT-199 is currently in phase Ib (NCT01685892).
These studies show benefit of obinutuzumab therapy in different lymphoma populations
using a variety of treatment paradigms, and point to the importance of this biologic
therapy in B cell lymphoma treatment.
There are a large number of new biologics competing for attention; just a few are discussed
here.
Another anti-CD20 antibody with breakthrough status is ofatumumab (Arezza). Approved in
2009 for use in rrCLL patients, this antibody is moving toward use earlier (i.e. in newly
diagnosed CLL) and in other patient subsets.
In May of this year, positive phase 3 data for ofatumumab were announced by GSK. Patients
with previously untreated CLL (n = 447) received ofatumumab plus chlorambucil (OF-C) or chlorambucil (C) alone. The study found that patients in the ofatumumab cohort experienced
a longer median PFS. That study will be updated at ASH (Abstract #528). Top line data is
here:
PFS
ORR
CR
MRD
OF-C
22 months
82%
12%
4%
C
13 months
69%
1%
0
Other studies on ofatumumab being presented at ASH include a phase 2 trial in combination
with dexamethasone, to treat high risk rrCLL patients (Abstract #2877). This study presents
a CR = 16% and PFS = 10 months, although the infection risk was quite high. Another
phase 2 study is testing the efficacy of ofatumumab in combination with the AKT inhibitor afuresertib (Abstract # 4175) in the treatment of high-risk rrCLL patients. In this small
study (n = 19) AEs were manageable (neutropenia, GI complications) but responses were
low: ORR = 42%, CR = 0, PR = 42%; 58% of patients had SD, and 26% of patients
progressed. Several other trials will also be updated (Abstracts #1645 and 4177).
An example of the high bar set by obinutuzumab therapy can be seen in several trials of
other biologics. Pfizer has developed an antibody/drug conjugate (ADC) called inotuzumab ozogamicin (InO). This is a humanized anti-CD22 antibody conjugated with calicheamicin, 
a potent cytotoxic. CD22 is expressed on most forms of NHL. The trial (Abstract #1821) 
is a phase 1 dose escalation trial designed to identify the MTD in combination with 
rituximab plus chemo (gemcitabine, dexamethasone, and cisplatin). AEs, mostly
cytopenias, causing dose reductions and dose delays established the MTD. Patients had 
rrNHL, with 21 DLBCL, 14 FL, 12 MCL, 4 SLL, 1 MZL, and 3 other indolent B-NHL.
At the MTD dose the ORR = 45% and the CR = 22%. Of the 55 patients enrolled, 12
(22%) discontinued due to AEs and 12 (22%) discontinued due to PD. These numbers
are a little worrisome although this is a difficult patient population to treat. It will be
important to see PFS and OS numbers as clinical development of this therapy continues.
An intriguing target for antibody development is CD37. CD37 is tetraspan protein expressed
on a variety of hematopoietic cells, and can transmit a cell death signal through its SHP-1
domain. Trubion engineered a modified antibody called TRU-016, now being developed by Emergent (see the 14 November issue of Blood – volume 122, p 3397 – for a brief description 
of this and other anti-CD37 targeting agents). Phase 2 data on TRU-016, now called 
otlertuzumab, will be presented at ASH. Otlertuzumab induces cell death directly (ie. by 
signaling cell death) and also through Fc-mediated cytotoxicity. The phase 2 trial recruited 
65 rrCLL patients who had failed between 1 and 3 prior therapies. The Abstract (#2860) 
presents data on 44 evaluable patients treated with otlertuzumab (OTL) or with otlertuzumab
plus bendamustine (OTL-b). The data are as follows:
treatment
ORR
CR
% progression
OTL
42%
4%
46
OTL-b
80%
20%
10
The % progression data refers to the responding patients only. AEs were in line with the chemotherapy treatment. A second study (Abstract #4165) provides preliminary data on
patients treated with otlertuzumab plus the anti-CD20 antibody rituximab (Rituxan). This
dual antibody therapy was given to previously untreated CLL patients. Preliminary data
suggest an ORR = 88%, and modest AEs. This trial will be updated at the meeting. These
early studies suggest that targeting CD37 is an attractive approach for CLL therapy.
BITE antibodies are bi-specific antibodies originally developed by Micromet. They have
received a lot of press following the 1.2 billion dollar acquisition of Micromet by Amgen. Blinatumomab binds to CD3 on T cells and CD19 on lymphoma cells, helping to direct the
T cells to recognize and destroy the tumor cell (BITE stands for BI-specific T cell Engager). Abstract #1811 has some very early data on blinatumomab treatment of rrDLBCL patients.
Lets be clear upfront that this is a tough patient group to treat. At the time of abstract
submission, 11 patients were enrolled with initial ORR = 57%. It will be very interesting
to hear updated results from this trial at ASH, including both efficacy and AEs, which at
first glance seem tolerable if unpleasant (including CNS toxicity).
MEDI-551 is an afucosyl-anti-CD19 antibody with augmented cytotoxic activity (due to the
lack of fucosylation of the antibody). An 83 patient Phase 1 trial (Abstract #1810) enrolled heavily pretreated rr CLL, DLBCL, FL, or MM (multiple myeloma). All of these B cell lymphoma types are CD19 positive. The ORR = 25%, with CR = 10.8% and PR = 14.5%.
50.1% of patients were characterized as SD. PFS was calculated to be 9 months. At first
glance the single agent responses are substandard; MedImmune is continuing development
of MEDI-551 in combination with chemotherapy.
A CD19 ADC has advanced to phase 2, in a combination trial with rituximab (Rituxan).
SAR3419 is a humanized anti-CD19 antibody conjugated to maytansin DM4, a cytotoxic
agent. It is under development by Sanofi and was licensed from ImmunoGen. This ADC
was given along with rituximab (Rituxan) to rrDLBLC patients (refractory to first line
therapy or relapsed after a prior therapy; Abstract #4395). ORR was low at 31% and 36%
of responders progressed by the end of the study. Sanofi plans to move this agent into
patient populations that may be more responsive.
So, here we have seen two anti-CD19 antibody therapeutics with rather poor efficacy
profiles.
I want to end with an old dog/new trick story concerning alemtuzumab. First studied many
years ago in the context of transplant rejection therapy, this anti-CD52 antibody lives on as
a treatment for hematological malignancies (CD52 is widely expressed) and, under the
brand name Lemtrada, as a therapy for multiple sclerosis. The long strange trip of this
nasty antibody (the side effect profile is not good) is the subject for another day. Of interest
at ASH however is a nice study looking at the utility of alemtuzumab for very high risk
treatment naive CLL patients (Abstract #2861). High risk is defined here genetically – these
are patients with genetic deletions or mutations known to be associated with poor prognosis. Without diving into the details, the investigators have shown that TP53 mutations had an
adverse prognostic impact and shorter PFS and this was overcome by alemtuzumab treatment. This then presents itself as a potential therapeutic for patients known to have this poor risk
factor.
If time allows I want to discuss the CAR-T technology, perhaps in the next section.