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 (Revlimid^tm and Pomalyst^tm, both from Celgene), are used with the proteasome inhibitors such as bortezomib (Velcade^tm from Takeda) or carfilzomib (Kyprolis^tm, 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

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 

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:

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.