Category Archives: $CELG

Snow Day Reading: The New Multiple Myeloma Therapeutics

There was a comment floating around Twitter that “Biotech was boring this week” and that’s true, it has been a slow news week. Sanofi took the ax to about 100 Genzyme site staffers, Bayer and J&J announced R&D reorganizations, another CAR T cell deal got done (China) and IPOs and follow-on financings were announced: business as usual.

In the background though, slow but steady therapeutic advances are being made that will impact long-term company values. The development of antibody-based therapeutics in multiple myeloma (MM) is one nice example. Among the hematologic malignancies MM is a major disease. The incidence in the US is ~30K yearly and the prevalence is ~85K. A quick glance at that math reveals a disease with pretty short-term survival, less than 5 years according a report produced by the Leukemia & Lymphoma Society in 2014.

The age of onset for MM is 70 years old in the US, and this is important because it limits some treatment options for many patients who are physically frail. Such patients may not be candidates for high-dose chemotherapy and stem cell transplantation (SCT) and even patients who are given this first line regimen will eventually relapse. Those patients are served by second line therapeutics, described below.

The huge advance is this field has been the development of non-chemotherapeutic drugs. The IMiDs such as lenalidomide and pomalidomide (Revlimidtm and Pomalysttm, both from Celgene), are used with the proteasome inhibitors such as bortezomib (Velcadetm from Takeda) or carfilzomib (Kyprolistm, from Onyx) along with steroids (dexamethasone, prednisone) in various combinations. “Triplets” are the preferred therapeutic, as exemplified by the combination of lenalidomide, bortezomib and dexamethasone.

At the ASH conference in December a large retrospective outcomes study of newly diagnosed MM patients was presented (link 1). Here is some of the data from that study:

Cohort                                                                         % Probability of 3 yr Survival

All ages (N = 1444) 63
       < 65 70
       65 to < 75 65
       ≥ 75 47
SCT
      Yes 77
      No 54
Triplet therapy
     Yes 69
     No 55
IMWG risk
     High 59
     Standard 66
     Low 76
del(17p)
     Present 53
     Absent 63

So a few things here to note: age of onset is a negative factor for survival, in part due to the inability to get the majority of elderly patients to autologous stem cell transplantation (ASCT). In addition to age of diagnosis, the International Myeloma Working Group

(IMWG) risk score is a composite of factors that determine outcome, and finally the presence of a chromosome deletion (called del(17p)) is known to be associated with significantly shortened survival.

In this study they demonstrated further that the use of triplet therapy vs. non-triplet therapy was associated with significantly prolonged OS regardless of IMWG risk but no improvement was noted for triplet vs. non-triplet therapy in patients with del(17p). Two things are clear from this study – one, we have patient subsets that remains underserved (the elderly and those patients carrying del(17p), and two, triplet therapy is keeping 70% of patients alive for at least three years.

What about patients that fail triplet therapy and who relapse and or are refractory to further treatment (rrMM)? They fare very poorly indeed, as shown here:

                               newly diagnosed                                           treatment failures 

MM survival curves

There are a variety of novel therapeutics moving forward in rrMM, including novel proteosome inhibitors, HDAC inhibitors, nuclear export protein inhibitors and any others. One class of therapeutic gaining significant attention are the antibodies directed to the MM cells. These include the antibodies to CD38 and other MM-selective cell surface proteins.

The lead therapeutic among the anti-CD38 antibodies is daratumumab from Genmab in collaboration with Janssen. The deal included a US$55 million upfront payment, an $80 million equity stake in Genmab, and milestone payments adding up to $1.1 billion or more.Daratumumab is a huMAX CD38 mAb which kills CD38+ tumor cells via CDC and ADCC activity and antibody-dependent cellular phagocytosis (ADCP) by macrophages. Additional activity may be due to apoptosis upon secondary cross-linking and modulation of CD38 enzymatic function (see ASH 2014 abstract # 3474). Daratumumab received the FDA’s breakthrough therapy designation in May 2013 for treatment of rrMM (for patients failing 2 lines of therapy).

When combined with lenalidomide and dexamethasone (len/dex), daratumumab produced an overall response rate (ORR) of 75% in the phase I dose ranging clinical trial. The trial was designed to accommodate an expansion cohort dosed at the MTD (maximum tolerated dose) of 16mg/kg. In the expansion cohort the ORR was ~ 92%.

In a phase Ib study daratumumab was combined with various regimens:

Screen Shot 2015-02-14 at 11.51.52 AM

These efficacy numbers are startlingly good. What will be really impressive is the associated duraton of response (DOR) and overall survival (OS) data once the trial is mature. In early February preliminary results from another Phase II study were announced. The study, called MMY2002, is listed as NCT01985126 on clinical trials.gov    (link 2). This two-part study enrolled 124 rrMS patients who had received at least three prior lines of therapy, including both a proteasome inhibitor and an IMiD, or were double refractory to therapy with a proteasome inhibitor plus an IMiD. The primary objectives of the study were to define the optimal dose and dosing schedule, to determine the efficacy of two treatment regimens of daratumumab as measured by ORR, and to further characterize the safety of daratumumab as a single agent. Two doses of daratumumab were compared in part 1, at 8 mg/kg and 16 mg/kg. The expansion cohort (part 2) received the higher dose based on interim safety analysis of the initial dose comparison.

The ORR was 29.2% in the 16 mg/kg dosing group with a DOR of 7.4 months. We can expect additional data to be presented at a medical conference this year, perhaps ASCO or ESMO, and ASH or EHA. These data will support the breakthrough therapy designation for daratumumab in rrMM and may lead to a 2015 approval in this patient population, i.e. based on the phase II results.

Additional daratumumab trials include 5 phase III trials in MM, including a series of studies in newly diagnosed MM, therefore, as front-line therapy, and a phase II trial ((LYM2001) in hematological malignancies. The study will evaluate daratumumab monotherapy in three different types of NHL, diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and mantle cell lymphoma (MCL).  The study is expected to start enrolling patients in 2015.

Sanofi Oncology is developing SAR650984 (SAR), is a human IgG1 antibody that targets CD38. TCD11863 (NCT01749969) is a phase Ib trial evaluating the combination of SAR with len/dex in rrMM: patients averaged six prior therapies. These prior therapies included the second line therapeutics lenalidomide (94%), pomalidomide (29%), bortezomib (94%), and carfilzomib (48%). Eighty four percent of patients were relapsed and refractory to a least one second line therapeutic. In the dose ranging phase, the highest SAR dose of 10mg/kg was well tolerated.

After a median 9 month follow up, the ORR was 58%, with a clinical benefit rate of 65%, including a 6% stringent complete response rate. In patients receiving the 10 mg/kg dose, the ORR was 63%. The median progression free survival (PFS) was 6.2 months for all evaluated patients but was not yet reached in patients who received fewer than three prior therapeutic regimens before entering the study.

Looking just at the 84% of who were relapsed and refractory to least one second line therapeutic, the ORR was 50%.

An interesting study presented at ASH in December suggested that Immunogenetic factors contributing to NK cell function influenced clinical activity in pts treated with SAR/LEN/Dex. Specifically, the presence of a high-affinity KIR3DL1, HLA-B Bw4-80Ile genotype was associated with high ORR and prolonged PFS. This suggests that the NK cell competency of the patient influences the ability of NK cells to become activated in the presence of tumor cells coated with SAR antibodies. This fascinating study (ASH 2014, Abstract # 2126) should stimulate investigation of mechanisms of NK cell activation that could be used in combination with SAR, assuming the presence of len/dex does not complicate the picture. There are additional clinical studies of SAR, listed here: link 3. These include a phase I/II study in hematologic malignancies.

In addition to daratumumab and SAR650984, Celgene and MorphoSys are collaborating on the development of the CD38 antibody MOR03087 (aka MOR202). This antibody is currently being investigated as monotherapy and in combination with len/dexamethasone or bor/dex in a phase I/II rrMM study (NCT01421186). The Morphosys licensing deal with Celgene included a $92M upfront, $60M equity investment and downstream milestones. Takeda is developing the anti-CD38 antibodies Ab79 and Ab19, currently in preclinical studies (link 4). Xencor has a CD3/CD38 bispecific program. The small private biotech Molecular Templates has an anti-CD38 antibody-drug conjugate program. There are likely other programs out there.

Elotizumab (ELO) from Bristol Myers Squibb targets a different MM antigen, SLAMF7 (aka CS-1). A presentation at ASH (abstract #2119) reported early results from a phase Ib study of ELO in combination with len/dex.ELO selectively kills SLAMF7-positive MM cells through both direct activation and engagement of NK cells. A multicenter, open-label, Phase Ib trial (NCT01393964) enrolled patients with newly diagnosed or rrMM and varying renal function. Renal function is a dose limiting feature of rrMM treatment and disease progression. ELO (10 mg/kg) plus len/dex was given in 28-day cycles until disease progression or unacceptable toxicity. 26 pts were treated, 8 with Normal Renal Function (NRF), 9 with Renal Insufficiency (RI), and 9 with End Stage Renal Disease (ESRD). 89% had received prior therapy (median 2 regimens). Prior bor, thalidomide, or len treatment occurred in 21 (81%), 11 (42%), and 9 (35%) patients, respectively. ORRs were 75% (NRF), 67% (SRI), and 56% (ESRD). Thirty-eight percent NRF, 56% of SRI, and 11% of ESRD patients had a very good partial response or better. Therefore ELO/len/dex was well tolerated and showed clinical responses in MM patients regardless of renal function.

These new therapeutics for MM will certainly complement the existing triple therapies, giving patients added hope and time. We certainly expect that one of the new combinations of antibodies and the second line “triple therapeutics” discussed above will have an even more dramatic impact on MM when given in the front-line setting.

In the meantime Janssen (J&J) and Genmab are poised to give Celgene some real competition in the MM space.

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
Phase
date filed
Combination
Indication
NCT01732913311/14/2012rituximabrr iNHL
NCT0153951232/12/2012rituximabrrCLL
NCT0120393029/15/2010rituximabuntreated CLL, SCL
NCT01980875311/5/2013rituximabuntreated CLL
or chlorambucilÿ
NCT01732926311/14/2012bendamustine/rituximabrr iNHL
NCT01980888311/5/2013bendamustine/rituximabuntreated CLL
NCT0156929533/27/2012bendamustine/rituximabrrCLL
NCT0164479917/17/2012lenalidomide/rituximabrrFL
NCT018384341,24/19/2013nonerrMCL
lenalidomide/rituximab
NCT0165902138/3/2012ofatumumabrrCLL
NCT0179647022/19/2013GS-9973rrCLL,MCL,iNHL,DLBLC
NCT0108804811/12/2010RituximabrrCLL or rrMCL or rr iNHL
Bendamustine
Ofatumumab
Fludarabine
Everolimus
Bortezomib
Chlorambucil
ÿLenalidomide
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.

Drug
Trial Number
Phase
date filed
Combination
Indication
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
and
NCT01558167
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.

LINKS TO THE #ASH13 ABSTRACT PREVIEW CHAPTERS @ SUGAR CONE BIO

ASH13 previews

Part 8.   ABT-199
Part 7.   CAR-T tech                        

Part 6b. new targets for Myelofibrosis           

Part 6a. Jak inhibitors in Myelofibrosis                       

Part 5.   Biologics for Non-Hodgkin Lymphomas              

Part 4.   New & noteworthy: CLL etc             

Part 3.   Btk and PI3K inhibitors for CLL      

Part 2.   Ibrutinib                              

Part 1.   Idelalisib

pre-ASH post on ADC technology:  here