Monthly Archives: June 2014

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Side Effect Profiles of Immune Checkpoint Therapeutics – Parts 2 and 3

Part 2 – The Border Wars.

One of the fascinating aspects of the toxicity of immune checkpoint therapeutics is that it is a lot of is triggered at the border between self and non-self, where non-self is everything that the immune system must encounter and sort through continuously. The sorting serves to identify pathogens and ignore non-pathogens among the myriad components of the microfauna and flora that inhabit these borders. The “sampling” of these ecosystems is continuous and highly reactive – one glass of unpurified water taken on foreign soil will teach you this lesson pretty quickly. When the immune system is unrestrained by blockade of CTLA4 and/or PD-1 it is not surprising that we see the breakdown of immune tolerance in these border zones.

There are three major surfaces where toxicity has been an issue: the skin, the gut mucosa, and the airspaces of the lung. Ipilimumab treatment can cause pretty intense inflammation of the skin, generally dismissed in the clinical trial literature as “rash”. In a pooled analysis of nearly 1500 patients enrolled in various ipilimumab clinical trials, 45% developed dermatological AEs considered drug related, and 2.6% (so 39 people) developed severe symptoms rating a grade 3-4 (where grade 5 is lethal) (see Tarhani, A. Scientifica 2013, Article ID 857519). A fair amount of the milder skin AEs can be ascribed to an anti-melan-A response, as this antigen is abundant in melanoma, the setting for the clinical development trials. In the Phase 3 registrational trials dermatologic AEs were reported in more than 40% of patients in the ipilimumab arms, and there were very severe AEs that cannot be ascribed to an anti-melan-A (i.e melanocyte) immune response. This is from Tarhani’s review of patients in the ipilimumab + gp100 (vaccine) and ipilimumab monotherapy arms having dermatological irAEs,

“of these, 2.1% and 1.5%, respectively, were grade 3 or higher … Severe, life threatening, or fatal immune-mediated dermatitis (Stevens- Johnson syndrome, toxic epidermal necrolysis, … full thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations; grade 3–5) occurred in 13 of 511 (2.5%) patients treated with ipilimumab. One patient (0.2%) died as a result of toxic epidermal necrolysis, and one additional patient required hospitalization for severe dermatitis… .”

That’s some rash. We note in passing that dermatologic AEs were see in a phase 2 trial of ipilimumab plus chemotherapy in non-small cell lung cancer (NSCLC) and so this is certainly not limited to the melanoma setting. PD-1 pathway antagonists also cause skin inflammation in both the melanoma and other settings, similarly suggesting that what we are seeing here are immune responses to antigenic stimulation that is normally immunologically inert. Nivolumab-induced dermatologic toxicity can be severe, but is less common than seen with ipilimumab therapy.

The issue of skin toxicity is well known clinically, and there are established treatment protocols requiring cessation of therapy and treatment with anti-inflammatories, usually steroids (i.e the REMS protocols). The gastrointestinal (GI, “gut”) AEs are also common, can arise suddenly, be resistant to therapy (corticosteroids, and rarely, anti-TNF antibody), and are of significant concern. Returning to the pooled analysis of ~1500 ipilimumab patients we see roughly half of the patients developing GI symptoms (this includes diarrhea). If we focus on grade 3/4 SAEs we have 10-12% of patients with GI disorders that include colitis, enterocolitis, intestinal perforations etc that can proceed to lethal septic complications. Of note, inflammatory infiltrates in the intestines include abundant T cells and neutrophils, showing that acute ongoing inflammation is occurring. GI toxicity is less common and less severe in nivolumab-treated patients, and this is true also of Merck’s anti-PD-1 antibody pembrolizumab and the anti-PD-L1 antibody MPDL3280A from Roche. Colitis is generally not a big issue, for example, GI SAEs are seen in less than 1% of nivolumab-treated patients. We might conclude here that other pathways are maintaining tolerance in the gut mucosa when the PD-1 pathway is blocked.

A different picture emerges when we consider AEs in the lung. Pulmonary toxicity is rare in the context of ipilimumab monotherapy, with only scattered case reports in the literature (see Voskens et al for a review of rare ipilimumab-induced AEs: link). Anti-PD-1 pathway therapeutics, particularly nivolumab, are associated with pneumonitis, which is inflammation of the lung tissues. In the monotherapy setting, both nivolumab and pembrolizumab causes pneumonitis in 3-4% of patients – the condition is generally mild and treatable. Of note this AE rate is consistent across indications (e.g. melanoma, renal cell). The anti-PD-L1 antibodies (Roche’s MPDL3280A and Astra Zeneca’s MEDI4736) have not been associated with pneumonitis to date, perhaps reflecting a unique profile. The recent data from the anti-PD-L1 antibody MEDI4736 trial in NSCLC presented a tolerable profile. While response rate was low, significant numbers of patients remained on therapy with stable disease (ASCO 2014, Abstract #3002).

More worrisome is the pneumonitis rate and severity in combination therapy particularly in the NSCLC setting where diminished lung function is already a concern (smokers with lung cancer can’t breathe). When nivolumab was combined with platinum-based chemotherapy in NSCLC the SAE rate jumped to 45%, with notable findings of grade 3/4 pneumonitis (7%) and acute renal failure (5%) (ASCO 2014, Abstract #8113). Nivolumab plus erlotinib was not associated with pneumonitis (ASCO 2014, Abstract #8022) but response rates were low as well suggesting that these therapies were not particularly additive. The combination of nivolumab with ipilimumab was most worrisome, with grade 3/4 pneumonitis (6%) now seen along with grade 3/4 SAEs of skin (4%), GI (16%) and others (16%) (ASCO 2014, Abstract #8023). Most problematic is that 35% of patients discontinued, and between 3 to 5 patients died due to drug related SAEs including respiratory failure (caused by severe colitis), epidermal necrolysis (in a patient with multiple SAEs) and pulmonary hemorrhage (pneumonitis). As indicated above, the anti-PD-L1 antibody MEDI4736 may better suited for combination therapy. A combo trial in NSCLS with anti-CTLA4 mAb tremelimumab is enrolling, so we’ll wait and see.

It’s fair at this point to take a step back and say “so what?” These are close to terminal patients with deadly cancers usually highly refractory to treatment, and we cannot expect a free ride. The unmet need is acute and urgent, and these therapeutics offer potential cures and increase in life expectancy – as shown very clearly in last weeks early termination of the Phase 3 trial of nivolumab versus dacarbazine due to the obvious overall survival advantage offered by nivolumab (see John Carroll’s story in Fierce Biotech here: link)

The problem is that the response rates we are seeing are generally low, the discontinuation rates high, and for anti-CTLA4 and anti-PD-1 therapeutics there is no clear consensus regarding the use of biomarkers to select patients most likely to respond. Therefore the actual percent penetrance of therapy in the patient cohorts becomes quite low. For those relatively few patients who respond well the outcomes can be sustained and robust. It is critical however to get these response rates up. The blockbuster combination of nivolumab plus ipilimumab in metastatic melanoma gives us a sense of what is possible, if the drugs are tolerable. It is also critical to understand how and why immune therapy can make subsequent therapy intolerable, as we’ve seen in case reports, or conversely, how and why prior therapies can cause such problems for patients going onto an immune therapeutic (see that Voskens review mentioned above). We’ve seen some the issues that can bedevil combinations in metastatic melanoma (with vemurafenib) and in renal cell carcinoma clinical trials (pazopanib) When we look at all of the combination clinical trials underway with these agents we have to wonder what surprises lay in store.

Part 3 – The Fifth Column.

The fifth column refers to enemies lurking within the boundaries of the state, in this case the human body. These are a mixed collection of AEs that can be difficult to understand. While we are used to see liver and kidney inflammation in the setting of cancer therapy, it remains a bit mysterious that immune checkpoint therapy can cause severe inflammatory responses in these organs, the most notable is probably the induction of hepatitis in patients treated with ipilimumab. Even weirder (for me anyway) are the endocrinopathies, headlined by pituitary inflammation, seen with both CTLA4 and PD-1 directed immunotherapies. Primary thyroid inflammation is also seen although less frequently. These are of course autoimmune targets in this setting, but the triggers are obscure, as is also almost always true in autoimmune disease. Somewhat remarkable is the emergence of a sometimes fatal but normally very rare condition known as autoimmune hypophysitis or lymphocytic hypophysitis, which is inflammation of the pituitary gland. Hypophysitis is a unique toxicity of immune checkpoint inhibitors, and has been been seen in patients treated with ipilimumab, tremelimumab, and nivolumab. Because the pituitary sits in the middle of the limbic hypothalamic-pituitary-adrenal axis effects on the thymus and adrenal gland are also noted, with adrenal insufficiency being a severe and life-threatening complication. It must be stressed that the frequency of this AE is stunningly high, reaching 17% in some trials, as the disease has been described only very rarely, with a good deal less than 1000 cases ever known prior to the introduction of immune checkpoint therapeutics.

So we won’t dwell on this, as clinicians now know what to watch for, and treatment paradigms have been developed. As mentioned earlier, treatment generally involves initiation of steroids to control to autoimmune response, and cessation of immune checkpoint therapy.

Let’s return to the consideration of combination therapy, which I think we all agree is essential if we are really to expand use of immune therapeutics in the treatment of these difficult cancers. Great hope has been placed in the combination of CTLA4 and PD-1 targeting agents with “safe” immune checkpoint modulators, notably the IDO-inhibitor from Incyte. We have very little information to date, but it is notable that the dose limiting toxicity in the first combination trial of ipilimumab and INCB024360 from Incyte (INCY) was liver damage as measured by ATL elevation. It may be that merely piling on ways of disrupting Treg activity will not help with the toxicity profile; in fact, one might make the prediction that this approach will make things worse in some settings.

We’ve remarked in passing on the apparently mild safety profile of the anti-PD-L1 inhibitors compared to the PD-1 inhibitors. This makes some sense, as the ligands are expressed by the target tumor cells, and this may be the main sink for the injected antibody, i.e. antibody may not be evenly bio-distributed but rather predominantly localized to the tumors. The concordance of anti-PD-L1 antibody activity with tumor PD-L1 expression is consistent with a direct and localized effect. The fact that there is less consistent concordance of anti-PD-1 antibody activity with PD-1 expression by tumor-infiltrating T cells suggests less specificity in the induced immune response, and this may be why we see autoimmune toxicity in the nivolumab setting. As CTLA-4 is exclusively T cell expressed, the same seems to hold true for anti-CTLA4 antibody therapy. So combining these may not be the most ideal way forward.

We will discuss alternative approaches next time, but first there is some new data on novel immune checkpoint therapies to consider. These are the TNF receptor superfamily proteins that we discussed last month (link): 4-1BB, CD27, OX40 and GITR. There is admittedly very little data to date. Pfizer’s (PFE) anti-4-1BB antibody PF-05082566 reached a safe dose in Phase 1 without undue toxicity signals (ASCO 2014, Abstract #3007). Pfizer disclosed combination trials with rituximab in Non-Hodgkin Lymphoma (NHL) and pembrolizumab (anti-PD-1). The BMY antibody urelumab was tolerated through its’ dose escalation cohorts, and ex vivo analysis showed activation of CD8+ T cells and NK cells (ASCO 2014, Abstract #3017). The Celldex anti-CD27 mAb also has demonstrated safe dose escalation, although to date without signs of clinical activity (ASCO 2014, Abstracts #3024 and #3027). Celldex (CLDX) claims planned studies in combination with nivolumab, ipilimumab, and the targeted therapeutics darafenib and trametinib.

As we discussed in an earlier post, 4-1BB, CD27, OX40 and GITR are evolutionarily closely related receptors. Biomarker studies such as the one performed in the urelumab trial will be essential in understanding how these immune stimulatory pathways will differentiate clinically and which will be safe in combination settings. We’ve reviewed the biology of this superfamily recently (see these posts) so won’t do so again until we get some more clinical data.

Next we will introduce some novel targets in the TNF receptor superfamily, revisit some apoptotic pathway “influencers”, and will swing back around to PD-1 and PD-L1 in some other solid tumor settings (not necessarily in that order).

stay tuned.

Side Effect Profiles of Immune Checkpoint Therapeutics – 1

Part 1 – wherein we introduce the issues

I think we are underestimating the impact of immune checkpoint mediated adverse events (AEs) and are too easily calmed by the notion that severe AEs (SAEs) can be managed or will reverse when drug is withdrawn. Indeed, we are beginning to see that the toxicity profiles of the anti-CTLA4 antibody ipilimumab and the anti-PD-1 antibody nivolumab will limit their use, at least in some settings. Anyone needing proof can look at Bristol-Myers Squibb (BMY) and their recent $50MM USD engagement with CytomX, a neat little Bay Area biotech that has developed “masking” technology for antibodies, called Probodies, that creates antibodies that are inert until they reach the tumor environment. Their website at http://www.cytomx.com/probodies.php has links to their Science Translational Medicine paper and also their 2014 AACR presentation.

So for their fifty million upfront, plus R&D support, BMY gets to apply the Probody technology to ipilimumab, and three other targets. Since BMY also owns nivolumab, we might make the reasoned guess that this is a second target, although that has not been disclosed and remains unclear. Another interesting target for masking is urelumab, the agonist anti-CD137 (aka 4-1BB) antibody. And it’s clear that there are other targets for which antibodies could benefit from being masked.

Why “mask” immune checkpoint antibodies? The issue is that these antibodies can induce immune responses that are off-target, that is, not directed at the tumor. Some off-target AEs induced by different agents are similar, some are quite unique and others appear only in combination settings. Lumping these all together as “immune-related” AEs (irAE) may be convenient but teaches us nothing about the underlying mechanisms.

So lets have a look at some general mechanisms.

Recent posts have concentrated on ipilimumab and the PD-1 pathway antagonists (see here) and have detailed some of the AE issues arising. Other toxicities have been seen with the TNFR agonists, such as 4-1BB and related receptors, whose biology and use are reviewed in another recent post (link).

Breaking irAEs down by class is helpful. The irAEs are most commonly associated with barrier tissues: skin, gut mucosa, the lung airways and the eyes. Less common are irAEs triggered in the context of “sterile” inflammation, that is, inflammation directed toward tissues and organs within the body and walled off from the outside environments. This class includes the endocrinopathies and abnormalities in liver, kidney and other organs. The third class captures central nervous system (CNS) toxicities. Some irAEs can appear with monotherapy, some are worse in the context of dual immune checkpoint blockade and some are associated with immunotherapy in the context of combination therapy with other types of drugs.

The cause of irAEs is very likely to be due to the breakdown of immune tolerance to commensal flora antigens and/or to self-derived antigens. We can look at the biology of the pathways targeted by ipilimumab and the PD-1 inhibitors for some clues to how this arises. The ipilimumab target CTLA4 normally acts as a shut-off switch for primary immune responses, blocking the activity of the closely related T-cell costimulatory receptor CD28, normally triggered by the B7 proteins, B7-1 and B7-2. The nivolumab target PD-1 acts as a similar stop signal but is associated with shutting off activated T cells by binding to its’ ligands PD-L1 and PD-L2. It is worth noting that these two families of receptors and ligands are closely related – CD28, CTLA4 and PD-1 are evolutionarily related receptors and B7-1, B7-2, PD-L1 and PD-L2 are closely related ligands. One consequence of this relatedness is seen in the ability of B7-1 to bind to and activated PD-1. Of interest, the evolutionary tales suggests a primordial single pathway that has diverged and specialized to control different aspects of the adaptive immune response. This is very similar to the situation we described for the closely related TNFR family members 4-1BB, OX-40, CD27 and GITR, and their ligands 4-1BBL, OX-40L, CD70 and GITRL.

The irAE story begins with ipilimumab, as does the immune checkpoint field. There are several mechanisms by which CTLA4 blockade might induce irAEs. The first is by lowering the threshold for activation of T cells, thereby allowing these cells to respond to antigens they would normally ignore. CTLA4 is expressed exclusively on T cells and regulates T cell activation. The second, related, mechanism is the breakdown of tolerance to antigens. On the surfaces of the organism antigens to which were have become tolerant (microorganisms, commensal flora) are routinely presented by APCs (antigen-presenting cells including dendritic cells and monocytes/macrophages) in the draining lymph nodes, Peyer’s patches, spleen and other lymphoid organs. Normally, these antigens are ignored. Furthermore, any aberrant T cells response to tolerant antigens is blocked by the action of T regulatory cells (Tregs). These Tregs “see” tolerant antigens and secrete immune suppressive factors to keep nearby T cells from becoming activated (T-effectors) and moving out into the environment to respond wherever antigen is encountered. It has been demonstrated that ipilimumab derails Treg function as well as pumping up T-effector cell function. As a consequence, in the presence of ipilimumab, T-effectors overwhelm any tolerance mechanisms and triggers immune responses to cells and tissues presenting antigens that are normally ignored. The setting for PD-1 pathway-mediated toxicity is similar although the details are a little different. PD-1 inhibition is mediated by expression of PD-L1 and PD-L2 on diverse cells types in the periphery (i.e. outside the lymphoid organs). PD1 is highly expressed on Treg cells. Peripheral tolerance is maintained by this system, and blockade of the system disrupts Treg function directly, and licenses T-effector cells for inappropriate responses to antigens normally ignored. The irAEs seen in the context of PD-1 blockade are generally considered less common than those seen in the context of CTLA4 blockade, suggesting that compensatory mechanisms of tolerance maintenance may be operative in the periphery.

Genetic deletion studies in mice can shed some light on these mechanisms. The CTLA4 gene-deficient (aka “knockout”) mouse dies within five weeks after birth from systemic autoimmunity. I’ve seen these mice several times – they have lymph nodes the size of large peas – and are half the size of wildtype littermates due to multiorgan autoimmune inflammation that is ultimately lethal. The phenotype of the PD-1 knockout mouse is less severe. These mice develop specific autoimmune diseases depending on the background strain of mouse use to derive the knockout. Autoimmune cardiomyopathy and lupus-like nephritis have been described. The PD-L1 knockout mouse has a very mild phenotype unless crossed back on strains of mice prone to autoimmunity, as was shown for lupus nephritis. The PD-L2 knockout mouse also developed renal disease although the mechanism differed from that of the PD-L1 knockout. Both manifestations required active challenge to induce disease, i.e. autoimmunity was not spontaneous.

So in this case the mouse genetic studies have previewed the human experience to the extent that CTLA4 blockade induces more toxicity than PD-1 blockade. As we’ll soon see, the combination of these immune checkpoint blockades can be more problematic that either given alone.

We’ll return with a toxicity by indication breakdown of irAEs induced by CTLA4 antagonists, PD-1 and PD-L1 antagonists and combinations of these agents with each other and other types of therapeutics. Then we’ll swing back to the TNF receptor superfamily for a look at the known and expected issues to be encountered there. We’ll finish with a few suggestions on novel ways forward – triggering T-effector immune responses to tumor without upending the systemic Treg environment. And as we do all that we’ll highlight a few key companies to watch.

stay tuned.

PD-1 Pathway Inhibition: Moving Beyond Melanoma

As we watch the clinical development of PD-1 pathway inhibitors we are struck by the ability of this approach to produce clinical efficacy in diverse cancers. Here we will briefly run through the rest of the landscape, starting with non-small cell lung cancer (NSCLC), then touching on metastatic renal cell carcinoma (RCC), glioblastoma (GBM), bladder cancer (UB), ovarian carcinoma and others. In many cases we are beginning to see the use of combination therapy, a setting that generally requires a careful look at toxicity. We’ll also look at the contentious issue of biomarker development for PD-1 and PD-L1 antagonists. The data are broken down into easy to understand bits, otherwise the whole thing is overwhelming.

The Emerging Role of PD-1 Pathway Inhibition in Lung Cancer

In the context of the often brutally aggressive tumors classified as the Non-Small-Cell Lung Cancers (NSCLC) progress is difficult and even incremental improvement in care is cause for celebration. Even so it was difficult to gather a consensus view of the clinical data being generated by the PD-1 pathway antibodies in NSCLC. In the melanoma setting (parts 1 and 2) our enthusiasm for PD-1 pathway inhibitors is driven by really terrific responses in some patients. The goal there is to improve the response rates while controlling toxicity. The clinicians argue, certainly with merit, that the responses seen justify the occasionally difficult toxicity. After all, all of their available therapies are limited by toxicity concerns, not only chemotherapy but also the small molecule targeted therapeutics. In this context, PD-1 directed therapies are well positioned.

It is not yet clear how these issues will play out in NSCLC. On the positive side, a subset of patients respond remarkably well to PD-1 pathway inhibition, and we may develop an understanding of how identify such patients. However, the overall response rates remain low, and impact on PFS and OS is small (see part 1 for a list of abbreviations). Complicating our understanding of the benefit of this class of therapeutics in NSCLC are three observations. The first observation is that tumor responses in this disease setting can be anomalous and may not be appropriately captured by standard RECIST tumor response criteria. The second observation is that severe toxicity can truly derail patients, and may even sensitize some patients to chronic toxicity that prevents application of other types of therapies. The third observation is that some targeted therapeutics for molecularly defined subsets of NSCLC patients are an attractive option to PD-1 directed therapeutics, and we don’t know yet if these can be combined.

The amount of data presented at ASCO14 was huge, and won’t try to cover it all.

There was a pretty dramatic response to the clinical trial data describing the utility of PD-1 pathway inhibitors in NSCLC. Bristol-Myers Squibb’s (NASDAQ: BMY) stock price dropped more than 6% from the start of ASCO on May 30th through the following week, and this on top of a long slide that started in March. Merck & Co (NYSE: MRK) stock jumped more than 2.5% at the same time. What was going on here? Let’s look at the estimated market sizes for three critical indications:Screen Shot 2014-06-18 at 6.55.32 PM

It is clear from the table that NSCLC is the largest patient population by more than 10-fold. It is also the case that NSCLC lacks the range of treatment options available to advanced melanoma and RCC patients. From the investor perspective then, NSCLC is a very big deal. Lets start there, and see how the emerging PD-1 pathway therapeutic class did in this setting.

Nivolumab anti-PD-1 antibody was studied in a number of clinical settings (ASCO14 abstracts #8024 and #8113). As monotherapy, nivo was generally well tolerated, and very effective for some patients. The ORR = 22% – 36% and a subset of patients had a durable response. Combining nivo with dual-platinum based chemotherapy increased the response rate but dramatically increased the SAEs, and in this early data did not appear to impact 1 year survival rates significantly. This table sums up some of the available data.

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Some patients responded very well – these were typically patients that had a non-squamous cell phenotype and whose tumors expressed PD-L1 and were therefore actively shutting down T cell responses by binding PD-1 on T cells. This figure is from a poster presented by Scott Gettinger (ASCO14 Abstract #8024).

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Tumor size is given on the Y-axis and duration is shown across the X-Axis, so for some responding patients the outcome is very good. In an effort to boost the effectiveness of immunotherapy for NSCLC, BMY ran a combination trial of nivo + ipi, as they had done previously in melanoma. They enrolled chemo-naive NSCLC patients, stratified by cell type into squamous or non-squamous groups, then gave these patients an induction regimen of nivo + ipi for 84 days (4 x 21 day cycles). The doses were either 1 + 3 mpk IV Q3W or 3 + 1 mpk IV Q3W, referring to the dose or nivo + ipi, respectively. Then the patients went onto a nivo maintenance schedule. The combination worked rather well, seeming to wipe out the disparity between the two cell types and overcoming some of the resistance seen in PD-1 tumors. Here are some illustrations of the data from Scott Antonio’s poster (ASCO14 Abstract #8023):

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As you can see, a fair number of patients have a sustained decrease in tumor volume or a stable disease course (no change in tumor volume over time). That’s a very nice result. Now the bad news. This combination therapy was nasty, a toxic brew. Discontinuation rates averaged 35% across the treatment arms with AEs including pneumonitis, liver damage, colitis, autoimmune nephritis (kidney inflammation & fibrosis), pulmonary hemorrhage, endocrinopathy, neuropathy, etc. Six patients (12%) died. We note that only 3 fatalities were directly attributed to the study drugs, but no one felt comfortable with these results. BMY’s stock price promptly dropped. We won’t know if the reaction was justified until other dosing and combo regimens are tried, but investors found another home, and that was with the competing drugs from Merck and Astra Zeneca (NYSE: AZN).

Immediately striking were the results from an NSCLC trial with the  anti-PD-1 antibody  pembrolizumab as monotherapy. Patients were selected based on positive PD-L1 staining on > 1% of tumor cells and given 2 or 10 mpg pembro Q3W or 10 mpk Q2W (ASCO Abstract #8077). The response rate was 26% or more, and the SAE rate was low (4%) although 18% dropped out due to AEs of any grade. Responses were durable with more than half of responders still on treatment at the time of data lock. A couple of things to note: these were treatment-naive patients, so presenting early in disease course. Second this figure (from the presentation by Naiyer Rizvi, ASCO #8007) shows maximum responses (ie. best response) and would not capture rebounding tumor size.

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As side note: the authors introduced an “immune response” criteria response rate because some patients would respond after having a new lesion appear (which would trigger the progressive disease (PD) score). Using these new criteria responses were even higher. We’ll see if these become more widely accepted.

AZN/Medimmune presented early expansion data on their anti-PD-L1 antibody, MEDI4736 (ASCO14 Abstract #3002 presented by Neil Segal) in advanced solid tumors. 84 patients with NSCLC were enrolled. The reported ORR was low but this was an accident of sampling as most patients had not gotten to their second screen yet and could not be scored as responders, per protocol. More impressively the vast majority of patients, across diverse tumor classes, remained on therapy.

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While it will be critical to see this data updated, the early read is very encouraging. Not waiting, AZN has initiated a pivotal trial in NSCLC and also a combo trial with their own anti-CTLA4 antibody, tremelimumab. We should be cautiously optimistic that the combination of anti-PD-L1 antibody with anti-CTLA4 antibody will have fewer tox issues than the anti-PD-1 combination, as mild tox appears to be a common feature of targeting the ligand rather than the receptor.

At this point of development, nivo has run into some problems in the combination setting, pembro looks promising, and MEDI4736 also looks promising. It will be very interesting to follow these story lines as they mature.

OK, RCC and other tumor types next, stay tuned.

A worthy campaign by patients for the National MS society

Healthline has launched a video campaign for MS called “You’ve Got This”. Patients living with MS can record a short video to give hope and inspiration to those recently diagnosed with MS.

You can visit the homepage and check out videos from the campaign here: http://www.healthline.com/health/multiple-sclerosis/youve-got-this

They will be donating $10 for every submitted campaign video to the National MS Society, so the more exposure the campaign gets the more the videos they receive and the more Healthline can donate to MS research, support groups, treatment programs, and more.

contact Maggie Danhakl • Assistant Marketing Manager         maggie.danhakl@healthline.com p: 415-281-3124 f: 415-281-3199

Healthline • The Power of Intelligent Health
660 Third Street, San Francisco, CA 94107
www.healthline.com | @Healthline | @HealthlineCorp
About Healthline: corp.healthline.com

PD-1 Pathway Inhibitors & Cancer Therapy – PART 2

Other PD-1 pathway therapeutics in advanced melanoma therapy.

Yesterday we focused on nivolumab, particularly in combination with ipilimumab, for the treatment of advanced melanoma. There are competing PD-1 pathway inhibitors that have now reported out substantial trial data. See part 1 for a list of PD-1 pathway therapeutics in development. Much attention has gone to Merck’s pembrolizumab, formally called MK-3475. The activity of pembrolizumab in melanoma is very similar to that of nivolumab, so it’s worth taking a closer look at the characteristics of the antibodies. Included here is pidilizumab, another anti-PD-1 antibody, developed by CureTech.

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Attributes of note include the different sources of the antibodies (fully human vs humanized murine antibody), different isotypes (IgG4 vs IgG1) and affinities ranging more than 200-fold from sub-100pM to 20nM. However, this is a small number of antibodies and it will be hard to discern how each of these attributes contributes to efficacy. Pembrolizumab closely resembles nivolumab except that the affinity for PD-1 is as much as 10 fold better. At the doses given it is difficult to know if this makes any difference, as drug levels may be saturating. We’d have to dig out target occupancy data from the trials to figure this out, but let’s look at the pembrolizumab results first, as it will become clear that this antibody has similar efficacy as nivolumab. How these therapeutics are being developed is different, as we’ll see.

The pembrolizumab (“pembro”) data reported at ASCO are from a huge Phase 1 clinical trial in advanced melanoma. Importantly, Merck made the strategic decision to stratify patients by prior exposure to the anti-CTLA4 antibody ipilimumab (“ipi”), from Bristol-Myers Squibb. This gave the company a jump on the field, allowing them to pursue FDA approval first for ipi-refractory patients. Due in part to the toxicity associated with ipi therapy, there are a lot of these patients. First, though, a brief look at the data, which has been widely reported. The data are compared to published data for nivolumab (“nivo”) treatment of ipi-naive advanced melanoma patients                 (http://jco.ascopubs.org/content/32/10/1020.long). A guide to the clinical abbreviations is included in part 1.

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If we focus on the ipi-naive ORR and 1 year survival data I think we have to conclude that these drugs are pretty comparable, and we’ll wait for additional data before trying too hard to differentiate these. That data will have to come from longer duration of ongoing trials and various combination studies. It is clear from the monotherapy data is that for advanced melanoma patients, anti-PD-1 therapeutics offer a chance at extended benefit. If we look more closely however,we see that in the nivo trial referenced above, half of the responding patients stopped therapy for reasons other than disease progression, most likely dropping off study due to AEs. It is true that 3/4s of the nivo patients stopping therapy maintained a response, some for extended periods. In the pembro study, the SAE rate was 12% but only 4% of patients discontinued therapy as a result of AEs, so that’s good. The catch is that in order to move ORR higher than 40%, combination therapy may be needed. As we saw with the ipi/nivo combo, this comes with much higher toxicity and drop-out rates. Of course the hope is that moving to earlier line therapy will boost response rates with the same or less toxicity and that data will come with time. As an aside, the question of ORR is the reason we have basically ignored the anti-PD-1 antibody pidilizumab, which had a 5-6% ORR. The 1 year OS was similar to the other anti-PD-1 therapeutics, but with such a low ORR it’s hard to believe this therapeutic from Curetech will gain much traction.

Anti-PD-L1 antibodies constitute the second class of therapeutics targeting the PD-1 pathway. These are in early clinical development in multiple tumor types, and will be addressed later. PD-L1 is also important in the context of predicting response to therapy in melanoma, and the utility of this marker as well as PD-1 is the subject of considerable discussion. When the ORR is 40%, it is helpful to select patients prospectively. We can take a close look at one of the smaller cohort studies to get a good look at this. In a study of responsiveness to pembro, Richard Kefford et al (abstract #3005) used an analysis of PD-L1 expression to demonstrate a remarkable difference in clinical response between patients who had > 1% tumor PD-L1 expression versus those who were PD-L1 negative. Biopsy was required in the 2 months preceding the start of pembro therapy; tumor PD-L1 expression was assessed by immunohistochemical staining. Patients received pembro at either 10 mg/kg Q2W, 10 mg/kg Q3W or 2 mg/kg Q3W. With a median treatment time of 23 weeks and ≥13 months follow-up, ORR was 41%, median PFS was 31 weeks and median OS was not reached. The 1-year survival rate was 81%, so this was a terrific cohort within the larger pembro study, likely due to the higher doses used. PD-L1 expression was associated with improved ORR by (51% vs 6%), PFS (median 12 vs 3 months) and 1-year survival rate (84% vs 69%). Note that while there were no treatment-related deaths; 14% of patients experienced drug-related SAEs (grade 3/4) again reflecting the aggressive dosing schedule.

In the large trial of ipi-naive patients treated with nivo, PD-L1 positive tumor staining was associated with ORR, but only weakly with PFS and OS. Why the data are less robust than the Kefford study is unclear. What is abundantly clear however is that there were profound responses in patients scored as PD-L1 negative, as shown in this screen grab from Dr Weber’s Discussant review of the melanoma oral poster session:

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These data suggest that caution should be exercised in the use of PD-L1 staining as a prognostic tool, and the search for better biomarkers of response continues.

We will revisit some of these issues as we move on to NSCLC, RCC, bladder, ovarian and solid tumors more generally.

PD-1 Pathway Inhibitors Reveal Unique Benefit/Risk Profiles Across Cancer Indications

Introduction

Anyone attending the immunotherapy sessions at ASCO earlier this month would have heard several distinct messages about PD-1 pathway inhibition in oncology. PD-1 appears to be a central control point for curtailing T cell responses in the peripheral tissues, similar to the role that CTLA4 plays in regulating initial T cell activation in secondary lymphoid organs such as the lymph nodes and spleen. Remarkable progress has been made in the 13 years since Gordon Freemen and colleagues first proposed in Nature Immunology that the PD-1 pathway was used by tumor cells as a shield against immune system attack (http://www.ncbi.nlm.nih.gov/pubmed/11224527).

It is clear that PD-1 pathway antagonists show tremendous promise in treating diverse cancers. Less clear is an understanding of why certain patients respond or don’t, what biomarkers might predict response, how to increase response rates, how to accurately measure response, and how to safely combine PD-1 pathway inhibition with other therapies.

Table 1 lists the PD-1 therapeutics in development (some of these therapeutics did not have updates at ASCO).

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As the table demonstrates, the PD-1 pathway inhibitors are being developed in diverse tumor types. As late Phase 2 data and Phase 3 data are coming out we can begin to see the real promise of these drugs in clinical responses measured in large numbers of patients. The amount of data presented at ASCO was a bit overwhelming so to simplify the landscape we can address each tumor type individually, when possible. Some terms we will use are given in the table below.

Table 2 defines the RECIST1.1 clinical response parameters and their abbreviations.

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To put these terms in perspective we can just consider that a meaningful clinical response is a measureable response to therapy (SD < PR < CR) that is durable and leads to an increase in PFS, which in turn allows a significant increase in OS. There are other terms used to describe clinical responses but these are the most common. We will start with some of the most recent data, and see where that takes us.

Part 1: Immune Checkpoint Combination Treatment of Melanoma 

The very first trials of PD-1 pathway inhibitors began with the investigation of nivolumab in metastatic melanoma. As such, there was an impressive amount of progress reported and we now have mature data on different therapeutics. To set the stage, we can consider the benefit shown by nivolumab monotherapy compared to standard of care treatment protocols, and also to ipilimumab (brand name Vervoy) an anti-CTLA4 antibody, also from Bristol-Myers Squibb (BMY). Ipilimumab is approved for the treatment of metastatic melanoma based on Phase 3 clinical trial data in metastatic melanoma patients that had failed prior therapy (a chemotherapy regimen). The trial compared ipilimumab to a tumor vaccine targeting the melanoma antigen gp100. Ipilimumab treatment improved median OS to 10 months versus 6 months with the vaccine treatment (which was no better than standard of care). The 1 year survival rate was 45%. ORR however was low, just about 10%. Also, adverse events (AEs) were a problem, and included autoimmune manifestations (colitis, pituitary inflammation) and some treatment-related deaths (2% of patients). In a separate study of treatment-naive metastatic melanoma patients, ipilimumab therapy was associated with an OS = 11.2 months and a 1 year survival rate of 47%, falling to 21% by year 3. Patients were given ipilimumab or placebo plus chemotherapy (dacarbazine), and then moved to ipilimumab or placebo alone if there was a response measured or if the initial therapy caused toxicity. One consequence of this scheme was that AEs went up dramatically, with 38% of patients experiencing an immune related, grade 3 or 4 severe AE (SAE). We dwell on the anti-CTLA4 antibody ipilimumab because it is the benchmark for other immunotherapies such as nivolumab.

Nivolumab therapy for advanced melanoma has produced impressive data, with median OS = nearly 17 months, and 1 and 2-year survival rates of 62% and 43%. ORR was 33%. AEs were significant if less severe than those seen with ipilimumab. Grade 3-4 treatment-related AEs were seen in 22% of nivolumab-treated patients. Immune-related adverse events (all grades) were seen in 54% of treated patients, and included skin, GI and endocrine disorders. However only 5% of patients experienced immune-related SAEs of grade 3 or 4 and there were no drug-related deaths. These data from Topalian, Sznol et al. from John Hopkins University School of Medicine were presented at ASCO last year and published earlier this year                       (http://jco.ascopubs.org/content/early/2014/03/03/JCO.2013.53.0105.full.pdf).

So with that as our backdrop lets update the state of PD-1 pathway antagonism in melanoma. One of the obvious next steps in the development of immunotherapy is to combine treatments and we saw dramatic long-term data from the combination trial of ipilimumab plus nivolumab in advanced melanoma. Early trial results presented at ASCO last year introduced 4 cohorts of patients given different doses of nivolumab and ipilimumab in combination, with an ORR across all four cohorts of 40% and a 1 year survival rate of 82%. Median OS had not been reached. SAE rate across the 4 cohorts was 53%. This quickly gets complicated so let’s define the cohorts. Numbers are doses of nivolumab and ipilimumab, respectively, in mg/kg: Cohort 1 (0.3 + 3), Cohort 2 (1 + 3), Cohort 3 (3 + 1), Cohort 4 (3 + 3). No data were presented for Cohorts 6 and 7 so we’ll skip those. Cohort 8 is designed to mimic the dose schedule chosen for later clinical trials.

Note that after the induction phase, patients are moved onto maintenance therapy, as show below.

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The slide is taken from the trial update presented at ASCO by Dr Sznol (Abstract #LBA9003). The data updates drove home several critical points. First, at the optimal dose rates of 1 + 3 and 3 + 1 the ORR ranged from 43-53%. The author’s introduce a new classification of clinical response to capture the observation that many patients are experiencing benefit while not strictly meeting RECIST1.1 criteria, this is termed “Aggregate Clinical Activity Rate” and reaches 81-83% in Cohorts 3 and 4 (note that Cohort 4 (3 + 3) was the maximum tolerated dose due to SAEs and will no longer be used). Perhaps more meaningfully, the percent of patients whose tumor burden was reduced by > 80% at 36 weeks was 42% across the cohorts. This is a remarkable number suggesting sustained clinical benefit. Indeed, in those patients who responded, the median DOR in Cohorts 1-3 plus Cohort 8 has not been reached. In Cohorts 1-3, 18/22 patients are still responding and 7 of those had discontinued therapy due to AEs (more on this below).

Dose cohorts were analyzed for impact on 1 and 2 year survival. In Cohorts 2-3 the 1 year OS = 94% and the 2 year OS = 88%. Most stunning of all was this data showing a median OS in Cohorts 1-3 of 40 months. Median OS in Cohort 3 (1 + 3) has not yet been reached.

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These data are best-in-class for treating advanced melanoma, and place ipilimumab plus nivolumab at the forefront of therapeutic options for these patients. The one outstanding issue remains that of toxicity. 23% of patients had to discontinue therapy due to toxicity, and one patient died of complications resulting from treatment. While Dr Sznol repeatedly pointed out that the toxicities observed are controlled by standard interventions, the problem is that these standard interventions include cessation of therapy. We have already learned from the ipilizumab experience that responses to immune checkpoint inhibition can take time, and for those patients who have to stop treatment after 1 – 2 doses due to toxicity, time may not be kind. It will certainly be beneficial to reduce SAEs so that more patients can remain on therapy.

Tomorrow we’ll look at other PD-1 pathway therapeutics and combinations in melanoma before moving on to other tumor types.

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