Category Archives: CC-292

Combination therapies for B cell lymphoma, part 2

Combination therapies for B cell lymphoma: CC-292 and idelalisib.

Lets begin by recapping where we were yesterday. We reviewed ibrutinib, the clear frontrunner in the race to bring new targeted oral therapies to B cell lymphoma physicians and patients. Ibrutinib is being developed by Pharmacyclics and Johnson & Johnson’s (JNJ) Janssen division, and was recently approved for the treatment of MCL. The drug is moving forward in many clinical trials spanning the B cell lymphoma space, and most of these trials are done in combination with other therapeutics, notably the antibody therapy rituximab (Rituxan). None of the trials are being run as collaborative efforts with other companies with one exception, a collaboration put in place with Onyx (now part of Amgen). None of the combinations are wholly owned by Pharmacyclics (PCYC) and JNJ. The interesting question of how best to tackle the cost of very expensive combo therapies in the oncology marketplace was raised.

Gilead (GILD) has developed the very exciting PI3Kdelta inhibitor, idelalisib (access to a recent review is here). Idelalisib data generated at lot of buzz at the American Society of Clinical Oncologists meeting (ASCO) and at ASH. While generally considered somewhat inferior to ibrutinib as a monotherapy, the phase 3 data in combination with rituximab was striking. The trial was run in rrCLL patients who had failed prior therapies (rituximab or chemo), so these are patients quickly running out of options. The ORR was 81%, but what was really impressive was the impact on PFS and OS. At 24 weeks twice as many patients were progression free in the idelalisib plus rituxumab arm (95%) versus the rituximab alone arm (46%). We’ll have to see how this therapy holds up, and we can expect interesting data at the 2014 conferences.

But back to our question for 2014 and beyond: how will combination therapies continue to develop for the treatment of lymphoma? Lets look at Gilead’s active clinical trials for idelalisib – note that some of these trials have already read out results.

Trial Number
date filed
NCT01732913311/14/2012rituximabrr iNHL
NCT0120393029/15/2010rituximabuntreated CLL, SCL
NCT01980875311/5/2013rituximabuntreated CLL
or chlorambucilÿ
NCT01732926311/14/2012bendamustine/rituximabrr iNHL
NCT01980888311/5/2013bendamustine/rituximabuntreated CLL
NCT0108804811/12/2010RituximabrrCLL or rrMCL or rr iNHL
Rituximab + Chlorambucil
Lenalidomide + Rituximab

At first glance this looks a lot like the list of trials listed for ibrutinib, and it is very similar. We see multiple combo trials with anti-CD20 mAbs (rituximab, ofatumumab), and several trials with Celgene’s lenalidomide (Revlimid), approved for MM. Again the choice of lenalidomide is interesting. The combination makes good sense biologically – lenalidomide should impact cells lodged in the bone marrow, where they would otherwise be resistant to anti-CD20 or idelalisib therapy. The question is how well is this combination therapy tolerated. The other interesting observation is that there are a fair number of trials in which the partner therapy is a chemotherapy (fludarabine, chlorambucil, bendamustine). Now these are all careful targeted to specific lymphomas in the last trial listed, NCT01088048, and you can look at the details here. I think this suggests that in addition to the high impact rituximab combinations, GILD is banking on seeing good efficacy in combination with standard chemotherapies. If so this will give the company an effective marketing and pricing edge.

Finally, and sensibly, we see a clinical trial in combination with Gilead’s own Syk inhibitor GS-9973. Gilead has advanced this inhibitor while also conducting a well publicized hunt for a BTK inhibitor to license, apparently without luck (and really, there just aren’t many good ones). The idea here is to knock out the Syk signaling to BTK, thus mimicking the effect of ibrutinib, in combination with eliminating PI3Kdelta signaling. If the combo is synergistic, and (importantly) well tolerated, GILD may be sitting on a unique therapeutic option. Again thinking of the marketplace, this could provide leverage with physicians and payers, although no one is suggesting that Gilead won’t price a combo as high as possible, as shown by the recent pricing of its HCV cocktail – and that drug at least can induce outright cures.

This brings us to Celgene, who is attempting to build combination therapies for lymphoma that it can control. Celgene is well behind ibrutinib in their development of CC-292, acquired with the Avila deal. Recently however they have adjusted the dosing schedule (to twice a day: bid) and are seeing reasonable ORRs between 55 – 67% depending on dose, as reported at ASH. The bid dosing regimens produced sustained responses through 7 months.

What is so interesting about the Celgene program is shown in the following table.

Trial Number
date filed
CC-292NCT017665831b10/29/2012lenalinomiderr NHL
CC-292NCT01732861111/14/2012lenalinomiderr CLL, SCL
CC-292NCT01744626112/5/2012rituximabrr CLL, SCL
AVL-292NCT0135193515/10/2011nonerr NHL, CLL, WG
lenalinomideNCT014006851,2April/May 2011bendamustine/rituximabCLL
lenalinomideNCT0193800139/5/2013rituximabrrNHL, rrFL
lenalinomideNCT0119957528/31/2010rituximabrr CLL
lenalinomideNCT0155677633/14/2012nonehigh risk CLL

What we see here is a nice focused effort on bringing forward CC-292 with perhaps lenalinomide. I don’t know the regulatory hurdles imposed since the withdrawal of lenalidomide from a CLL trial earlier this year (but please comment if you do), and so the issue may be moot, but the idea is a good one – to rationally develop combinations that are wholly owned.

We can make some predictions.

JNJ will buy a clinical stage compound suitable for further development with ibrutinib. This could be an antibody targeting B cell lymphoma antigens (CD20, CD22, CD19, etc) or another small molecule asset.

Celgene will make similar moves but may take assets at a slightly earlier stage, maybe IND ready or Phase 1.

Gilead will continue development of its Syk inhibitor, but I suspect will also license clinical stage assets in order to diversify around idelalisib.

Assuming success in the early stage studies in relapsed/refractory patient populations, Gilead will aggressively position idelalisib for use with chemo in treatment naive patients.

If you have different ideas feel free to send those along. Next there will be just a short take on Abbvie, as they are on a slightly different course.

stay tuned.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

NCT01980654210/24/2013rituximabuntreated FL
NCT0152051921/25/2012rituximabhigh risk CLL, SCL
NCT0161109035/15/2012rituximab/bendamustinerrCLL, rrSCL
NCT0177684031/24/2013rituximab/bendamustineuntreated MCL
NCT01479842111/1/2011rituximab/bendamustinerr DLBCL,MCL,iNHL
NCT0188687236/24/2013noneuntreated CLL
v rituximab/bendamustine
NCT01974440310/28/2013R-CHOPrr iNHL
v rituximab/bendamustine
NCT0188685916/24/2013lenalidomiderrCLL, rrSCL
NCT0182956814/9/2013lenalidomide & rituximabrrFL
NCT0195549919/27/2013lenalidomide & rituximabrr iNHL

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

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

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

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

NCT020131281,212/11/2013ublituximabCLL, MCL
NCT0157870734/11/2012v ofatumumabrrCLL
NCT0184172321/24/2013noner Hairy Cell leukemia

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

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

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

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

Stay tuned.