Lymphoma | Pharma Strategy Blog

The CLL Landscape is rapidly a’changing…

By MaverickNY on October 10, 2013

Yesterday evening, Gilead announced that the Data Monitoring Committee (DMC) had recommended early stoppage of the 116 trial, which looks at idelalisib in relapsed/refractory disease in patients who are not eligible for chemotherapy. These patients usually have comorbidities or are elderly and frail, and often receive chlorambucil or rituximab alone. The study compared the combination of idelalisib plus rituximab versus rituximab alone.

Fortunately, the early stoppage was for a good reason – the interim analysis demonstrated a statistically significant improvement in PFS in favour of the combination over rituximab alone. Adverse events were consistent with previous experience of the drug.

I would imagine that Gilead will seek a filing this year in the near future (presumably once the Government shutdown is over) and we can possibly expect a late breaker at ASH. This is good news for CLL patients and at least six months earlier than expected.

Based on this information, I would also expect approval for idelalisib in relapsed/refractory CLL by ASCO next year, a year ahead of schedule. The company have already filed in relapsed/refractory NHL, so the FDA will have a solid safety database from which to make an informed decision.

The frontline CLL trial, presented by Dr Susan O’Brien at ASCO, compared the combination of rituximab plus idelalisib to rituximab alone and is still ongoing. I’m hoping we will have an update on this at ASH in December.

Gilead have undertaken a smart strategy to date with most of their trials in combinations with approved therapies such as rituximab and bendamustine, which will make it easier for community oncologists, who treat the majority of CLL patients, to integrate a new therapy in their existing treatment options. Sometimes, getting these physicians to switch to a new single agent drug from long established practices is harder and slower than people realise.

Adding something to the existing standard of care is a much easier sell to community doctors, who usually have have older, less fit patients than the Academic physicians, who put their younger, good performance patients into clinical trials where possible.

In the runup to ASH, the CLL market is now getting very interesting – and crowded.

Recall that Roche announced their phase III results for GA-101 (obinutuzumab) in the frontline setting for the same patient segment at ASCO. They are expected to gain approval soon, probably before ASH and have breakthrough status in this indication.

Pharmacyclics and J&J previously filed ibrutinib in 3 indications and have breakthrough therapy designation in CLL, NHL and mantle cell lymphoma (MCL) as single agent therapy. Approval is also expected this year. There is no doubt that they have a potent and effective single agent in these diseases.

Obviously, a lot of people have wondered whether a combination of ibrutinib plus idelalisib will lead to better overall response rates than either alone. I actually asked this question of the companies presenting at a NYAS meeting a year or two ago, and predictably, they weren’t too enthusiastic.

Why?

Well, it’s much harder for two companies to collaborate on joint trials than it is for a company to manage two agents of their own. To this end, I’m always arguing that companies with a broad and deep pipeline are more likely to win out in the long run if they have the components for logical combinations in the disease being evaluated in house.

What does all this mean?

Source: Gilead

What this means is that Gilead and Roche are well placed in CLL and indolent NHL, since Gilead can combine idelalisib (PI3K) with their SYK inhibitor (upstream in the pathway like BTK), GS-993, and Roche can potentially combine GA-101 (anti-CD20) with their Bcl2 inhibitor, ABT-199/GDC-0199.

Many of you will recall the preclinical data at AACR earlier this year looking at Gilead’s two agents and demonstrating some synergies worthy of testing in the clinic. This combination is already in the clinic with two phase II studies currently enrolling in refractory CLL, iNHL and other lymphoid malignancies.

What we should look for is not just the initial response rates and PFS from individual trials, but what the impact of inhibiting two or more pathways will have on survival with subsequent therapies over time. Resistance in leukemias and lymphomas can sometimes take a while to take effect and there are multiple targets to aim at, so cycling different novel combinations by line over time will be interesting to watch.

Strategically, it’s not just about the isolated data with one drug in one line of therapy – we may well see a large improvement in 5 and 10 year survival rates for CLL and iNHL in the long term, with a better quality of life for patients – that’s what oncologists really want to see in the future.

These new developments will undoubtedly put pressure on Infinity, since their PI3K delta/gamma inhibitor is much further behind and will need to define a clear and compelling proposition to differentiate IPI-145 from not only idelalisib (PI3K delta), but also obinutuzumab and ibrutinib.

One thing is clear – such a fertile seam of new therapies – ibrutinib, obinutuzumab and idelalisib in the near term, followed by ABT-199 and IPI-145 in the medium term, is going to change the CLL and iNHL landscapes forever. That’s a good thing for patients, caregivers and oncologists.

ASH is going to be the meeting of the year at this rate… for those of you needing an overview of the leading agents in the CLL/iNHL landscape, check out this pre-ASCO overview here.

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Update on iNHL and CLL – idelalisib, obinutuzumab and ibrutinib

Yesterday, Gilead announced on their 2Q Earnings Call that they plan to file their PI3K delta inhibitor, idelalisib (formerly CAL-101), with the FDA later this year in indolent non-Hodgkin’s Lymphoma (iNHL). Discussions with both FDA and EMA have already been initiated based on the phase II results in CLL and iNHL.

Many of you will recall the CLL data presented at ASCO by Dr O’Brien (MD Anderson) and Jennifer Brown (Dana Farber), followed by the iNHL data update presented in Lugano by Dr Salles (Lyon Sud).

The single arm NHL study 101-09 evaluated idelalisib (150 mg BID) in patients (n=125) who were refractory to rituximab and alkylating agents. In other words, there is a high unmet medical need for a new alternative therapy option.

As background, recall that previous trials with ofatumumab (4 prior regimens) and bendamustine (2 prior regimens) demonstrated an overall response rate (ORR) of 22% and 76% respectively, with a duration of response (DOR) of around 5.8 and 10 months.

In study 101-09, patients received approximately 4 prior regimens (maximum was 12) and are therefore more comparable to the ofatumumab study in terms of prior therapy. Interestingly, 65% also received bendamustine in addition to rituximab and alkylating agents, while 63% received an anthracycline.

Instead of an ORR in the expected 20-30% range, the actual number was an impressive 53.6%.

What about the DOR you may be thinking? 11.9 months.
Progression-free survival (PFS) was 11.4 months.

The waterfall plot tells a bigger picture:

Source: Gilead

Side effects were similar to those previously reported, with diarrhea, fatigue, cough and nausea being the most common. The only grade 3 event in double figures was diarrhea (10%). Almost half (48%) saw raised liver enzymes (ALT or AST), with 13% experiencing grade 3 or more. Hematologic events were mainly decreased neutrophils (53%) with a quarter (26%) experiencing grade 3 or more.

The company also has three phase III trials in CLL ongoing.

In particular, Study 116 (idelalisib plus rituximab versus rituximab alone in patients unfit for chemoimmunotherapy) is nearly enrolled. The interim analysis is expected in the fourth quarter this year. This trial is a similar population to the German CLL11 study in patients with co-morbidities that compares obinutuzumab and rituximab with chlromabucil to chlorambucil alone.

No doubt if the interim analysis is promising, then further Health Authority discussions will ensue with regards to the CLL approval path for idelalisib.

What does all this mean?

Gilead have gathered solid phase II data for idelalisib in refractory iNHL, an area of high unmet medical need. Whether this would be considered for Accelerated or full approval isn’t yet clear, since there are no surrogate endpoints. It will be interesting to see how the FDA view the data and make an informed decision. No doubt we will hear more later in the year pending discussion with the FDA and their perspective on the data.

My experience from extensive market research and KOL interviews in CLL is that patients with co-morbidities tend to be treated with either chlorambucil or rituximab, both as single agents. Thus having two new therapies ie obinutuzumab and idelalisib (in different combinations) potentially available in the near future would transform this particular disease segment, create new standards of care, offer more therapeutic options and raise the bar for future entrants.

Pharmacyclics and J&J are also in the mix in CLL and NHL with their BTK inhibitor, ibrutinib, having Breakthrough designation and FDA filings have also begun for that compound. These markets will soon become very competitive and it will be interesting to see how the landscape plays out given the lack of biomarkers available to help with decision making. Obviously, the labelled indications will drive initial usage. After that, no one is clear yet on how oncologists will ultimately decide on three different therapies, each with good data. I do think it’s good to see clear progress, that’s ultimately the important thing from a clinical perspective.

Roche/Genentech have Priority Review and a PDUFA data of December 20th for obinutuzumab in front-line CLL, as well as Breakthrough Designation. This could be very timely for the company given the ASH meeting in early December. Pharmacyclics’ ibrutinib is expected to receive rapid approval for CLL and refractory mantle cell lymphoma (MCL). In the meantime, if Gilead file for iNHL by year end, then idelalisib could be commercially available in the first half of 2014.

In addition, both idelalisib and ibrutinib appear to have decent efficacy in CLL patients with 17p deletions, a small subset that tend to have a poorer prognosis.

All of these exciting developments will make it more challenging for other possible agents in development by demonstrating good activity in areas that might have previously appeared attractive as a fast track to market strategy. For patients and oncologists, a surfeit of riches is no bad thing!

Exciting times in CLL: an ASCO 2013 interview with Dr Susan O’Brien

At the recent ASCO 2013 meeting in Chicago, I had the great pleasure to interview Susan M. O’Brien, MD who is the Ashbel Smith Professor in the Department of Leukemia at the University of Texas, MD Anderson Cancer Center in Houston, and someone who is making a difference to the lives of CLL patients.

I first met Dr O’Brien over ten years ago when I was at Novartis Oncology in new products working on bringing to market what was then known as STI571, and subsequently became Gleevec.

In the same way that tyrosine kinase inhibitors forever changed CML, the treatment of Chronic Lymphocytic Leukemia (CLL) is set to undergo a major transformation over the next few years.

I hope you will enjoy this video interview in which Dr O’Brien discusses some of the CLL data presented at ASCO ’13 and shares her perspective on several of the new targeted agents in development. It’s an exciting time in CLL!

After several months of free/open access, this video is now viewable on Biotech Strategy Blog Premium Content.

Tumor Lysis Syndrome – what is it and why is it important in cancer research?

By MaverickNY on February 18, 2013

After the hullabaloo on Friday regarding AbbVie’s suspension of the ABT-199 trials following not one, but two, unexpected deaths from tumor lysis syndrome (TLS), a few people asked what is this condition and what causes it?

In simple terms, lysis is a medical word used to describe the break up or breakdown of cells – whether through decomposition, destruction, or dissolving. Thus, we have hemolysis, which is the destruction of red blood cells with the release of hemoglobin.

Tumor lysis, however, is a medical emergency whereby the sudden production of massive amounts of potassium, phosphate, and nucleic acids into the systemic circulation overwhelms the body’s garbage disposal units, the liver and kidneys. Urgent hospital treatment is usually required, often diuretics can be helpful to flush out and dilute the excess potassium (too much can slow or stop the heart beating), but sometimes kidney dialysis is also needed to speedily remove the excess production of the potassium. Death can unfortunately (but not always) result.

TLS is most common in aggressive, fast growing (high grade) lymphomas and acute leukemias (e.g. ALL), but is less common in indolent disease such as chronic lymphocytic leukemia (CLL).

Given that AbbVie were testing their Bcl2 inhibitor in CLL, where TLS is rarer, some might think two deaths from TLS a surprise, especially given the positive results reported at the recent American Society of Hematology (ASH) meeting in December (more about the ABT-199 data).

This is not the first time TLS has been reported in leukemias though. Carl June (U Penn) presented the data on their chimeric antigen receptor therapy (CART), a collaboration with Novartis, in CLL and also childhood acute lymphoblastic leukemia (ALL) at ASH. Their lead therapy, CTL019 (formerly CART19), also leads to TLS in both ALL, where it is more common, and CLL patients, although he did state in the Ernest Beutler lecture that the patients received urgent renal dialysis and recovered.

Interestingly, Dr June described the TLS as occurring not immediately, but delayed until 20-50 days post infusion. Given what we know about autologous cellular immunotherapy, a delayed response is not a surprise, but in line with our scientific knowledge to date, since it takes a while post apheresis to activate the T-cells.

You can see from Dr June’s slide that the serum levels of creatinine and uric acid spiked around day 20, but the patient was hospitalized for TLS a few days later:

It is possible that the TLS occurs in CLL as a result of rapid efficacy and on target effects – in other words, the treatment is doing it’s job of killing the cancer cells, perhaps a little too well.

Final thoughts…

We will have to wait and see what happens with the larger randomized phase 3 trials for both ABT-199 and CTL019:

We don’t yet know whether the effect in ABT-199 is a dose-schedule issue or a compound structure issue (especially given the reformulation from the original navitoclax molecule).
If TLS is a persistent toxicity issue and efficacy is durable, then it may well limit both potential treatments to Academic centers with experience and resources to quickly monitor and treat such sudden events in future.
These are exciting molecules but care is clearly needed in managing the toxicities.

Contrast these approaches with ibrutinib, a tyrosine kinase inhibitor that targets Bruton Kinase, where the effects appear to be slow but steady inhibition of a key target driving CLL proliferation. TKI therapies are very Community oncology friendly in comparison, particularly for indolent diseases. Although the Bcl2 and CART therapies look very promising, they may need a more careful and judicious approach to reduce the risk of sudden deaths from TLS.

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A surfeit of riches in CLL and NHL: on bruton kinase and PI3K delta inhibitors

By MaverickNY on June 27, 2012

This week I’m attending an interesting 2-day conference on PI3K at the New York Academy of Sciences (NYAS).

It brings together a broad faculty of researchers in the field looking at novel aspects of the PI3K-Akt-mTOR pathway in depth.

One aspect that has become clear with these compounds is that there’s probably more that we don’t know than we do – it’s a highly complex network of nodes and cause-effect that needs to be unravelled.

We do know a few things though, for example, PI3K and mTOR are often activated in advanced disease and can cause resistance to therapy as we have seen with aromatase inhibitors in ER+ disease and trastuzumab in HER2+ breast cancer. We also know that inhibiting PI3K or mTOR can lead to activation of compensatory pathways that serve to drive oncogenic signalling and tumour survival. It’s complicated!

The most advanced agent in the PI3K class is probably Gilead/Calistoga’s GS-1101 (formerly CAL-101), which is a delta isomer inhibitor being evaluated in B-cell hematologic malignancies such as mantle cell lymphomas (MCL), indolent NHL and CLL. After promising phase I and II trials, it has now moved into randomised controlled phase III trials.

Yesterday, Langdon Miller (Gilead) gave a nice overview of the GS-1101 program. One couldn’t help but marvel at the waterfall plots obtained to date, along with the before and after pictures of a women in her 40’s with refractory CLL – a dramatic difference – she looked like a completely different person! Of course, there are a number of questions that need to be addressed next:

Is survival prolonged in heavily refractory patients accustomed to immunotherapy?
How reproducible and durable are these responses on a large scale?
How can the redistribution of the lymphocytes be addressed? Will chemotherapy help here?
Is there value in combining a PI3Ki with immunotherapy in earlier stage disease?

All of these questions are being evaluated in the next phase of the GS-1101 clinical trials. I was impressed with the progress and where Gilead are going with the compound.

There are some questions that remain in my mind though. CLL and iNHL have an embarrassment of riches in pipeline agents at the moment, with several promising compounds in development.

The obvious rival to PI3K delta inhibitors are the bruton kinase inhibitors (BTK) such as Pharmacyclics/J&J’s ibrutinib (PCI-32765), which reported impressive data at ASH last December, followed up by new data at ASCO on the combination of ibrutinib with an approved CD20 antibody, ofatumumab.

This got me thinking…

1) If we assume that both agents are lucky enough to get approved by the FDA sometime in the near future, how will oncologists and hematologists decide which agent to give which patient? Can patients be stratified in any way in order to define selection for treatment?

2) Is there any data on whether combining these agents together would be synergistic? (I don’t think so, yet)

3) If a PI3K-delta and a BTK inhibitor were synergistic preclinically, what are the chances emerging of a combination trial between the four companies involved in the development of GS-1101 and ibrutinib? Sadly, a cynic would shake their head and say very low, but we need an answer on 2) from academic research before we get too excited.

4) What are the mechanisms of adaptive resistance in patients to both classes of agents in CLL and NHL? If we know the answer to this critical question, then rational combinations could be investigated further.

5) Would combining GS-1101 with CD20 antibody immunotherapies such as rituximab and ofatumumab be an interesting approach to see if better response rates and outcomes will be achieved? These are indeed being planned, along with a combination with bendamustine, another drug often used in relapsed/refractory NHL and CLL.

6) How will sequencing be important? If a patient is eligible for either therapy, which one should be tried first? This area is rather murky right now.

We’ve come a long way so far with both of these compounds, but there’s still an even longer way to go before we have some clarity on how they might change clinical practice and help improve outcomes for patients with NHL and CLL.

This is definitely an exciting area to watch out for, even if we have more questions than answers right now.

ASH 2011 Update #2 – Non Hodgkins Lymphoma

By MaverickNY on December 21, 2011

I’ve been busy with other things offline since the last blog update from the American Society of Hematology (ASH) meeting in San Diego, but will be catching up on my notes from the conference over the next few days.

In addition, my colleague Pieter Droppert has already posted his topline impressions of the meeting on the companion Biotech Strategy Blog, which readers may be interested in:

Meanwhile, I thought it would be a good idea to look at the pipeline developments in non-Hodgkin’s lymphomas (NHL) that I particulalry liked at ASH:

PI3K inhibitors

Pieter’s choice of PI3K as a hot topic turned out to be rather prescient given that:

a) Intelikine announced last night that the company is being bought by Millennium-Takeda in a deal worth $190M upfront with $120M in additional milestone payments. This is a great transaction all around, enabling clinical development to now begin for Intellikine’s two remaining PI3K-mTOR and selective isoform inhibitors and since Takeda have research facilities locally in San Diego, this will enable work to continue with minimum fuss and relocation.

b) As of this morning, Exelixis announced they have licensed their PI3K-delta inhibitor in preclinical development to Merck. This deal features an upfront payment of $12 million, but the company will be eligible for potential development and regulatory milestone payments for multiple indications of up to $239 million in the future.

Another PI3K inhibitor in the news is Calistoga’s CAL-101 (now owned by Gilead), a delta selective isoform inhibitor being evaluated in indolent NHL. At this meeting, the phase I data was presented in a poster. The patients enrolled to date (n=37) included those with follicular lymphoma, small lymphocytic leukemia and marginal zone lymphomas, all of whom had received prior therapy for their disease. In this study, CAL-101/GS-1101 was given in combination with rituximab and/or bendamustine to determine the safety profile.

The big question is whether the combination with chemoimmunotherapies would lead to added or overlapping toxicities – the authors, de Vos et al., concluded that answer was no and a good efficacy signal was seen:

“GS-1101-based combination therapy with rituximab and/or bendamustine offers major and rapid reductions in lymphadenopathy.”

On the basis of this study and a prior phase I trial that determined the dose (150mg/BID), further continuation of the program in this indication appears warranted:

“The data from this trial will be used to design Phase 3 combination studies of GS-1101 in patients with iNHL.”

Anti-CD20 monoclonal antibodies

Rituximab was the first targeted cancer drug following its approval back in 1997 and has shown how important targeting CD20 has been in lymphomas and more recently, chronic lymphocytic leukemia (CLL). At this meeting, we saw an interesting new development in lymphomas from Roche/Genentech in GA101 (obinutuzumab). This is essentially a follow-on biologic to rituximab. In a previous post prior to ASH, I looked at the key questions that need to be addressed in order to displace rituximab, namely more activity in rituximab refractory patients, more efficacy/better side effect profile up-front or broader activity across several diseases.

What are the key differences between rituximab and obinutuzumab you might ask and does this impart any clinical benefit?

Well, rituximab is a humanised type I monoclonal antibody, whereas obinutuzumab is a humanised type II glyco-engineered antibody, both target CD20. What’s the difference between Type I and II? Well, according to Robak, 2009:

“GA-101 binds with high affinity to the CD20 type II epitope, resulting in the induction of antibody-dependent cytotoxicity that is 5- to 100-fold greater than observed upon treatment with rituximab.”

The proof of the pudding is always in the clinical data, especially randomised head-to-head trials. There were over a dozen abstracts on GA101 at ASH, but the most important one in this context was a phase II GAUSS trial from Sehn et al., which randomised patients with indolent B-Cell NHL to receive either rituximab or obinutuzumab in the relapsed setting:

Gauss trial schematic courtesy of Roche

And the result? The authors concluded that:

“Treatment with GA101 in patientss with relapsed NHL resulted in higher response rates compared to rituximab as assessed by both investigators and the IRF at an early time point.

GA101 was well tolerated, although a higher rate of IRRs was noted, the majority were grade 1/2 in severity and did not result in significant differences in treatment discontinuation.”

Where IRR is infusion related reactions.

This data is promising for obinutuzumab, but still very early – we will still need to see what happens in a larger scale phase III trial with more patients before we can draw more definitive conclusions. That said, I found the GAUSS trial data very encouraging indeed.

Bruton’s Kinase Inhibitors

In the first update, I highlighted how Bruton’s Kinase inhibition (BTK) was one of the exciting new emrging pathways in chronic lymphocytic leukemia (CLL), but new data was also presented on the leading BTK inhibitor, PCI-32765 (Pharmacyclics/J&J), in lymphomas.

The preliminary phase II data in mantle cell lymphoma (MCL) presented by Wang et al., in 48 patients (29 bortezomib-naive, 19 bortezomib-exposed) with a median of two prior treatment regimens (range:1-5).

Initial efficacy data was reported:

“The objective response rate (ORR) is 67% (16/24); ORR is 58% (7/12) in the bortezomib-naive cohort and 75% (9/12) in the bortezomib-exposed cohort.”

The side effect profile seen to date was also described:

“Serious AEs (SAEs) have occurred in 8/39 patients (21%); 2 SAEs (1 rash, 1 febrile neutropenia) were considered potentially related to PCI-32765.”

I thought these results were encouraging – with good tolerability and encouraging signs of efficacy – certainly worthy of exploring in a randomised phase III trial in this indication. This is an agent we are probably going to hear a lot more about in the near future.

And finally…

There were a lot of new developments emerging at this meeting, particularly in the poster sessions and also in both phase I and II trials. It was impossible to keep up with everything, so this post is just a flavour of some of the abstracts either of us did manage to take in.

The challenge, as always, with ASH is their insistence of holding all the critical oral sessions on biology and therapy in leukemias, lymphomas, myelomas and myeloproliferative diseases almost on a single day, making it absolutely impossible to see/hear all the new and exciting data. Monday is, therefore, always a manic day. It’s a strange contrast from the long lulls on the Sunday where some of the oral sessions could have been hosted, perhaps the biology sessions, thereby freeing up a more flexible schedule for the clinical data on Monday. There is some weirdness and also dismay in seeing a biology and clinical session for the same topic (eg CML, Multiple Myeloma, Lymphomas or FLT3 in AML) clashing. Not everyone is a specialist, certainly the community oncologists who attend are not. This is silly scheduling and means that people presenting in a biology session often miss the clinical update for a trial they were a PI in, while attendees like me are regretably forced to choose from one or the other.

Sadly, not everyone can stay until Tuesday morning when a few more key oral sessions that include new data are held, for a meeting that began on Friday. This is issue compounded by no virtual meeting facility, one of ASCO, AACR, ECCO and even the NY Chemotherapy Symposium’s great online service whereby you can catch up with sessions you missed later. For me, this is a critical and integral part of modern cancer meetings.

I hate missing out on great or important data and hope that ASH will seriously consider virtual meeting access for future meetings – it really does help attendees – otherwise if you didn’t catch the sessions they are gone forever! Personally, I was still watching (and enjoying) presentations I missed at AACR and ASCO in July, long after both meetings finished, and really appreciated their excellent webcasts/virtual meetings.

One of the sad things for me was it turned out to be the first time in many years that I skipped the Plenary session as there were some odd choices this year that simply didn’t resonate with me. For example, making Mylotarg, a drug withdrawn by the FDA recently, one of the meeting highlights made little sense to me because:

a) it will have no immediate clinical or even scientific impact for the practising oncologist and
b) there were far more dramatic results that I thought were worthy of broader dissemination

Overall though, this was a good ASH meeting from the point of view of exciting new data in phase I and II trials; clearly the oncology pipelines are beginning to show some early promise, but it was disappointing not to see more of them prominently highlighted. There were quite a few other abstracts I liked, but this overview should give a good flavour of some of the novel agents emerging for the treatment of NHL.

For those wanting information on Hodgkins Lymphomas, I’ll cover those in a separate post as there was too much data to cover both in one post.

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ASH 2011 Update 1: Bruton’s Kinase Inhibitors (BTK)

By MaverickNY on December 15, 2011

This year’s American Society of Hematology (ASH) meeting heralded a wealth of new information on pipeline compounds in early development. Although a lot of people were excited about myelofibrosis and the battle between Incyte’s ruxolitinib and YM Bioscience’s CYT387 (more on these in a separate update), the area that intrigued me most was the Bruton’s Tyrosine Kinase (BTK) inhibitors in B-cell lymphomas.

Background on the science behind the BTK pathway:

I’ve been following these novel agents for a while and was fascinated by two abstracts from the ASCO and ASH meetings last year. It became clear that BTK is a valid target in B-cell lymphomas after Advani et al., (2010) demonstrated at ASCO the effect of BTK inhibitor PCI-32765 monotherapy on responses in patients with relapsed aggressive NHL.1

Later that year, Ponader et al., (2010) showed that PCI-32765 abrogates BCR- and nurselike cell-derived activation of CLL cells in vitro and in vivo.2

Between them, these two abstracts offered a solid rationale for investigating BTK inhibitors in B-cell lymphomas and CLL.

Where are we now with clinical development?

Fast forward to ASH this year, Dr Susan O’Brien presented the initial phase I/II data in chronic lymphocytic leukemia (CLL), which was well worth waiting for the last day of the conference to hear. She took us through the concept of the how the BTK pathway fits into B-cell malignancies:

BTK Source: Dr Susan O’Brien ASH 2011 CLL oral session, reprinted with permission 3

Essentially BTK is a critical part of the BCL pathway that leads to proliferation, so targeting it leads to cell death or apoptosis:

“BTK is a Tec family kinase that is required for B-cell activation mediated by BCR signaling. The essential role of BTK in normal B-cell development is evidenced by the clinical syndrome X-linked agammaglobulinemia, in which BCR signaling is abrogated by mutations in BTK.

Signaling from the BCR is also believed to be required for the maintenance of cell division and survival in B cell malignancies, presumably via downstream phosphorylation of PLC-gamma by BTK, ultimately leading to the activation of the anti-apoptotic transcription factor NF-kB and the kinase ERK.

Additionally, BTK may also play a role in the pathogenesis of B-cell malignancies by regulating integrin-mediated migration and adhesion, through regulation of malignant cell response to lymph node-derived chemotactic factors, such as CXCL12 and CXCL13.”

What does the latest data show?

Here’s a quick overview of the preclinical and clinical data I managed to see at ASH. There were over 2,000 posters over three days, plus a day and a half of simultaneous oral sessions, so it was quite hard to keep up with the sheer volume of it all!

In mantle cell lymphoma (MCL) the preclinical data looked encouraging:

Ponader et al., (2011) provided a nice overview of the initial PCI-32765 preclinical data in mantle cell lymphoma (MCL) in a poster presntation.4

They concluded that MCL cells express surface IgM and BTK, which is involved in BCR signalling. In this study, PCI-32765 successfully blocked BTK function and inhibited MCL proliferation, except in resistant cell lines. The former explains why there were responses in patients, while the presence of the latter suggests that additional BTK independent pathways exist and need to be elucidated.

I think that figuring the mechanisms of resistance out is important because it will help suggest possible rational combinations with BTKi therapy in advanced disease.

In CLL, the initial phase I/II clinical data is early, but promising:

Over the last 18 months, patients with CLL (n=117) have been enrolled into five trials, although the interim data was reported in the two relapsed/refractory arms (asterisked arms) at this conference, at two different dose cohorts of PCI-32765, given orally daily at either 420mg (n=27) or 840mg (n=34):

PCI

Source: Dr Susan O’Brien ASH 2011 CLL oral session, reprinted with permission5

The overall response rate (ORR) of 67-68% for both doses in the relapsed, refractory setting showed impressive activity and a clear sign that the BTK target is a valid one in this setting. Although the CR rate was low (<5%), the majority of patients saw PRs in this setting. Those with bulky disease (common in advanced disease) tended to do better.

There were also dramatic changes in the tumour burden, with the majority of patients seeing a greater than 50% change from baseline. Sustained improvements in blood counts were also reported. What particularly caught my attention was the activity in patients with known poor risk factors such as 11q and 17p deletions, who tend to have noticeably poorer outcomes. Obviously this is only a small phase I/II trial and we will have to see what happens in a larger scale randomised phase III study to see if the results are reproducible.

Typical side effects were diarrhea, cough and fatigue (any grade and grade 2+). The most common grade 3 adverse events were pyrexia, fatigue and diarrhea. Bearing in mind this was a heavily pre-treated population, many of whom had received prior immunotherapy, I thought the results were promising. The downside of immunotherapy is that while it has shown effectiveness, it does leave patients, especially the elderly, rather beaten up. The lack of grade 4 events in CLL was especially encouraging in this group.

What are the main BTK inhibitors in development?

Johnson and Johnson announced they were licensing Pharmacyclics PCI-32765 compound for nearly a $1B just prior to the meeting.6

Based on the data seen over the last two years, I thought they got a steal – this looks like it will be a very promising agent indeed. However, while they are clearly the leading BTK inhibitor, based on the sheer breadth and depth of their program, they aren’t the only one in this niche.

Avila Therapuetics also have a BTKi in early development, AVL-292, but they only have one phase I trial ongoing that I could find. The initial phase I data in B-cell malignancies was also presented in a poster at ASH.7

You can see why J&J licensed the Pharmacyclics agent – it’s much more advanced in the clinic than the others:

BTK
What does all this data mean?

Emerging data on BTK inhibitors has started to show that they produce consistently effective and well tolerated agents in B-cell malignancies such as NHL, MCL and CLL. I think this is a new class we are going to hear a lot more about over the next few years, either alone or in combination with other therapies.

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Follow the American Society of Hematology ASH conversations!

By MaverickNY on December 10, 2011

It doesn’t seem a full year since the last American Society of Hematology (ASH) meeting took place, time has certainly flown by!

For those interested, I posted a review what I think will be hot topics at this meeting

In the meantime, to enable easy reading of the tweets and discussions here in San Diego for those both attending and following remotely, I’m aggregating the tweets around the official hashtag, #ASH11.

You can follow the conversations over the weekend through Tuesday in the widget below:

If you have any questions please do add them in the comments below or feel free to tweet me, @maverickny on Twitter.

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What’s hot at the American Society of Hematology 2011?

By MaverickNY on December 9, 2011

Greetings from the annual American Society of Hematology (ASH) meeting in San Diego!

The palm trees and warm sunshine here were a most pleasant welcome after the bitter chill in Texas.

Having just arrived here from the San Antonio Breast Cancer Symposium, I thought it would be a nice idea to do a quick preview of some of the new and interesting data that I’m interested in at this conference and share some of the hot topics that I’ll will be following over the weekend:

Ponatinib in refractory CML
In myelofibrosis, rixuluximib and CYT-387
Velcade and pomalidomide in multiple myeloma
Obinutuzumab, PCI-32765 and alisertib in lymphomas

Let’s take a quick look at these topics in turn.

CML

The updated phase II PACE trial is expected to be presented at this meeting. Ponatinib is a potent second generation BCR-ABL inhibitor that also targets FLT3 and FGFR. The initial indication is expected to be in relapsed, refractory CML after prior treatment with a minimum of two TKIs, although many are likely to have received imatinib, dasatinib and nilotinib, so a heavily pre-treated population. Patients with advanced CML or Ph+ ALL received ponatinib in a single arm open-label trial. The other thing to note is that this agent is the only TKI so far shown to target the rare T315I mutation and these patients were included in the study.

If the results continue to hold up for durability with no additional safety signals since FLT3 and FGFR may induce off-target side effects, then I’m expecting Ariad to file ponatinib for accelerated review with the FDA, based on phase II data in relapsed and refractory CML, sometime in 2012. This is an exciting new agent and it will good for patients with CML to have an additional option in this setting.

MYELOFIBROSIS

This year has seen a lot of interest in myelofibrosis with Incyte’s ruxolitinib (Jakafi) receiving FDA approval recently. The drug was approved largely on the basis of its ability to reduce spleen size, which is one of the complications of the disease. The updated phase III COMFORT-1 data is being presented on Monday and my assumption is that we will see an improvement in overall survival with ruxolitinib.

There has been a lot of interest in YM Bioscience’s agent, CYT-387, which caused a stir at ASCO after initial data suggested that it may be able to reverse anemia associated with the condition.

Now, I’m not sure of the exact mechanism behind this phenomenon, since both compounds target JAK1 and JAK2, so the anemia response may be an artifact or a real effect. If the anemia effect is real, then I’m expecting to see the hemoglobin levels to go up rather than down, as we saw with Jakafi. The poster on Monday may well tell us more about what’s happening here and also I’m hoping to speak to some myelofibrosis thought leaders to see what their perspective is.

MYELOMA

Multiple myeloma has seen real improvements in overall survival over the last 10 years with the introduction of bortezomib (Velcade) in the upfront setting and lenalidomide (Revlimid) in the refractory and maintenance settings. Currently, a new kid on the block, Onyx’s carfilzomib, is currently being reviewed by the FDA in the refractory population, although we likely won’t know the decision until 1Q next year. If approved, it may offer physicians a new option to extend outcomes even further in advanced myeloma.

There is another agent not far behind, pomalidomide, which is a third generation immunomodulatory agent similar to lenalidomide. Celgene are presenting key data at this meeting and I’m looking forward to seeing how the data is progressing. I’m expecting this compound to show good efficacy in advanced myeloma, as it is thought to be more potent than Revlimid.

The phase III multiple myeloma study that is of great interest is the VISTA trial, which will be presented on Monday and compares the combination of Velcade, melphalan and prednisone (VMP) with melphalan and prednisone alone (MP). The five year data in treatment naive multiple myeloma will inform us which combination has superior overall survival and side effect profile and what can be expected in terms of secondary primary malignancies (SPM) with the triple versus double combination over longer term follow-up.

LYMPHOMAS AND CLL

For me, the big lymphoma story at this ASH is probably going to be GA101, now named obinutuzumab. It’s a CD20 antibody similar to, but also different from, rituximab, making it ideal for testing in NHL since the proof of concept is already established for the CD20 target.

My critical questions related to this agent’s development are:

Will it overcome rituximab resistance and work in refractory patients?
Will it work more effectively than rituximab earlier and prolong outcomes further?
Will it have fewer side effects than rituximab?

If any of the above are true, how does obinutuzumab work differently than rituximab and does that explain any of the differences?

Not all of these questions will be answered here at this ASH meeting, but I’ll discuss these issues in more detail once the data is available.

Finally, there are a couple of other compounds in early development for lymphomas that I’m really interested in.

The first is PCI-32765 (Pharmacyclics), a bruton kinase inhibitor (BTK), while the second is Millennium and Seattle Genetics’s aurora kinase A inhibitor, alisertib. These are relatively new mechanisms of action in lymphomas and intriguing scientifically.

I’ll write more about these particular agents in depth as the data becomes available, but they’re worth watching out for over the weekend as the wires hit the news sites.

Meanwhile, you can follow the conversations at the American Society of Hematology meeting on Twitter using the official hashtag of #ASH11.

Do check back for daily updates here in the blog for the hot (and sometimes not so hot) data. I’ll also be posting a video review of the important news next week.

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A year in the life of Pharma Strategy Blog

By MaverickNY on October 31, 2011

Last week brought the first anniversary of this blog since moving to WordPress as a platform, but as luck would have it, I was snowed under with more work than usual.

Several people have asked about the stats here recently, so it seems a good time as any to do an annual review. Although this blog has been up and running since 2006, it only started on WP on October 24th 2010.

In the last twelve months, PSB has seen the following activity:

614K reads, with around 50-60K reads per month
337K visitors, approx. 30K visitors per month

The busiest day was 6th June, with nearly 5K reads, thanks to a kind link from Matt Herper of Forbes Health. Ironically, the interim and eagerly anticipated MDV3100 phase III data from Medivation is now due before the end of the year. More on that when the announcement comes out!

What were the most popular posts? Here’s the Top Ten on Pharma Strategy Blog from the last year based on hits:

In some ways, the popularity of these particular posts are no surprise, since if you asked me to name the hot topics in oncology this year, I would have said:

ALK in lung cancer
BRAF and CTLA4 in melanoma
Abiraterone in advanced prostate cancer
ADCs and brentuximab

It wasn’t all positive though, as the ongoing PARP story has been notable largely for the negative data. That may change in the future as scientists and clinicians grapple with finding the right targets and sub populations to aim these therapies at.

I was particularly pleased to see that PI3K resonated with the audience as this one of my favourite pathways, although we still have a long way to go to crack the nut with this target.

A big thank you to everyone who read PSB, posted comments, shared articles or the many email exchanges that have taken place; it is much appreciated and I hope that you have enjoyed reading my thoughts and commentary.

Come December, I will post the annual review and predictions for 2012, but in the meantime, normal blog commentary on cancer related topics will resume tomorrow.

Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts from the ‘Lymphoma’ category