Category Archives: Sanofi

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
      Yes 77
      No 54
Triplet therapy
     Yes 69
     No 55
IMWG risk
     High 59
     Standard 66
     Low 76
     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    (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.

Inflammation, autoimmunity & oncology drug development questions for 2014: Multiple Sclerosis

In thinking where Multiple Sclerosis (MS) treatment is heading, and what critical question to ask, it bears quickly reviewing advances made in the past year. I’ll be brief however, as this subject has been extensively covered. 2013 saw the approval of multiple new therapies for relapsing and remitting MS (rrMS), the common form of this disease. BG-12 was approved under the name Tecfidera in March in the US, and more recently in the EU. This is an oral drug from Biogen Idec with a decent efficacy profile and tolerable side effects. This drug is widely seen as having blockbuster potential (greater than 1BB in annual sales) and has been taking market share from Novartis’ Gilenya, an oral drug approved in 2010 and having similar efficacy as Tecfidera but a more difficult toxicity profile. Tecfidera may also be taking patients who would otherwise go onto Tysabri, Biogen’s flagship MS therapy and considered to be the most efficacious MS drug. Tysabri also has toxicity issues that complicate its use, especially for longer than 2 years. Since both Tecfidera and Tysabri are part of Biogen’s portfolio this is seen as a net positive (thinking of investors here who, like myself, are BIIB long).

Sanofi won approval in the EU and (eventually) the UK for its reformulated version of terifluonimide, the active metabolite of leflunomide, an old immunosuppressive drug developed for RA among other indications. The drug was approved under the name Aubagio in the US in 2012. It is hard to guess where this drug will end up in the MS medicine chest. Early estimates had Aubagio hitting 500MM-700MM USD a year in worldwide sales by 2015-2016. Currently Aubagio is running at about 120MM Euros for 2013 (165MM USD) and its prescription trajectory was impacted by the Tecfidera launch (much like Gilenya). On the other hand this is a once a day oral with a pretty clean toxicity profile and a positive impact on relapse rate, so it may be a good choice for relatively mild MS patients who are coming off of a beta-interferon therapy or off Copaxone and need something more potent. At the moment Aubagio trails the other oral MS drugs.

Sanofi’s more potent rrMS therapy hit a wall in the US just a few days ago. Lemtrada was rejected by the FDA, shutting this drug out of the US market for now. Lemtrada was approved in the EU earlier in 2013. This is yet another old drug, the anti-CD52 mAb once known as Campath or alemtuzumab. Sanofi/Genzyme pulled this drug from the lymphoma market, anticipating more value in MS. This appears to have been a poor bet but Sanofi had smartly hedged this bet when it acquired Genzyme, by creating warrants whose value was tied to Lemtrada approval and sales milestones. Those warrants have dropped in value form $24 to under $1 at last check.

I admit to some ignorance as to why this drug hit such a snag with the FDA. I’ve been told that the doses used for MS therapy are much lower than those that had been used to treat lymphoma, and the side effect profile was tolerable. On the other hand the FDA briefing documents used language regarding safety that was very negative, similar to what we heard a few years ago regarding cladrabine, an oral drug from EMD Serono with truly nasty toxicity. There were also questions regarding the design of Aubagio’s Phase 3 trials, which clouded the efficacy claims.

For much more on these drugs please see my earlier post on MS orals (here).

So where are we now? The array of drugs available to neurologists to treat MS is remarkable and the arrival of Tecfidera may provide long-term protection for many patients. The trio of Tecfidera, Gilenya and Aubagio means that there are real choices for patients who can benefit from oral therapy. Finally, more severe patients can turn to Tysabri for even greater efficacy, assuming that the toxicity is managed, particularly in regards to PML, a demyelinating disease caused by JC virus infection in the CNS. Biogen has done a good job of risk mitigation for PML. I predicted some time ago that we would see PML associated with the use of Gilenya as well (here) and to date have happily been proven wrong.

Ok, questions for 2014:

  1. Will novel pathogenic pathways underlying rrMS be discovered and will these yield useful therapeutic targets? Large scale GWAS and epigenetic analyses of MS have been published recently and it will be interesting to see if new therapeutic approaches will emerge from these data.
  2. What will the next generation of S1P antagonists yield? Gilenya is in this class but acts promiscuously on S1P receptors. Will more specific S1P antagonists bring equivalent efficacy with less toxicity? This is a very active area and we will begin to see advanced clinical development soon. BAF312 (siponimod, Novartis) and ONO-4641 (ONO Pharma) are in late Phase 2. These are S1P selective modulators and showed benefit in Phase 2. These drugs still cause cardiovascular abnormalities however.
  3. What will the next generation of NRF2 modulators yield? Tecfidera acts in part as an NRF2 agonist, eliciting potent anti-oxidative and anti-inflammatory effects. Can a specific NRF2 agonist provide next generation drugs for rrMS? I’ll note in passing that antagonism of the NRF2 regulatory protein Keap1 is also an attractive drug development option.
  4. Drugs available to date provide benefit primarily by preventing lesion growth, new lesion formation (aka relapse) or both. Will we see drugs developed that promote the repair of damaged tissue, more specifically, promote remyelination of nerve axons before they are completely destroyed? We are beginning to see a real focus on repair mechanisms, and a therapeutic that could stop disease and promote repair would be transformative.
  5. Finally, what about progressive MS? As far as I know, no tested drug has improved outcomes in progressive MS (please correct me if I’m wrong here). In progressive MS there are no remissions and relapses, its just chronic progressive destruction of the CNS. Lemtrada had been touted as one drug that might help here (however, without clinical evidence), will there be others? Notably, siponimod is listed on as recruiting for Phase 3 in secondary progressive MS (SPMS), and ONO-4641 is listed as recruiting for Phase 3 in both rrMS and SPMS.

MS is a disease whose treatment has drastically changed patient’s lives in the past 20 years. I was at Biogen in 1996 when Avonex was approved, and treatment options at that time were ineffective and did not prevent disease relapse. Avonex and other beta-interferons marked the beginning of a radical transformation in the treatment of MS. We’ve come a very long way in 20 years. I think we still have a long way to go.

SnapShots, American Society of Hematology Abstracts – Part 3

Part 3. Additional studies featuring small molecule inhibitors for Chronic Lymphocytic Leukemia and other B cell lymphomas.

November 18, 2013

The American Society of Hematology Meeting will take place in New Orleans, December 7 – 10, 2013. The abstracts are available at

Lets start with other compounds targeting Btk, PI3K and related kinases in the BCR signaling cascade. In part 1 of this series we looked at Idelalisib, a PI3Kdelta (d) inhibitor, and in part 2 we reviewed Ibrutinib, a Btk inhibitor. In both of those reviews we focused on data from CLL trials, as CLL is the most common B cell malignancy.

Other Btk inhibitors are moving through the clinical development process. Abstract #1630 presents Phase 1 data for relapsing/refractory Non-Hodgkin’s Lymphoma (NHL) patients, including CLL and SLL patients. CC-292 is a covalent inhibitor of Btk developed by Avila and acquired, along with that company, by Celgene. The Phase 1 is a dose escalation/dose schedule trial, with various doses between 125 and 1000 mg given once (qd) or twice (bid) a day. The maximum tolerated dose (MTD) was not reached and AEs were as usual in these trials, with cytopenias being the most common toxicity. The patients enrolled were rrCLL/SLL with high-risk characteristics, as were outlined in Part 1. Of 83 patients enrolled, response data are shown for the 55 efficacy-evaluable patients who had at least a PR (so, 66%). These patients were treated at the highest 4 dose levels: 750 mg qd, 1000 mg qd, 375 mg bid and 500 mg bid (qd = once daily and bid = twice a day). Across these 4 dose groups the ORR = 60% and all responses were PR. Some patients showed evidence of reduction of nodal (lymph node) disease as seen by a reduction in size of the nodes. Abstract #4169 lays out the pharmacodynamic (PD) assays that will likely be used in support of further optimization of this drug’s PK/PD profile. The assays include the familiar Btk autophosphorylation and PLC-g2 phosphorylation assays. Applied to the Phase 1 trial, the PK/PD analysis shows that BID dosing is preferable for CC-292, with 94% target coverage achieved at trough over 24 hours vs 83% target coverage (+/- 17%) at trough with qd dosing. This is important data that has already been applied to further clinical trials underway.

I’m hopeful that optimized dosing will allow CC-292 to achieve higher response rates. Looking beyond lymphomas, Celgene investigators will present preclinical data showing that CC-292 given in combination with a proteosome inhibitor carfilzomib had activity in Multiple Myeloma models (Abstract #682) suggesting other therapeutic areas for the development of Btk inhibitors.

Ono Pharmaceuticals will be presenting Phase 1 clinical data for ONO-4059, a covalent BTK inhibitor (Abstract #676). The trial enrolled 16 high risk rrCLL patients for a dose escalation study (20 – 320 mg). ONO-4059 is shown to have a half-life in circulation (T1/2) of 6 hours. Remarkably, PD analyses shows Btk target coverage of 100% at 24 hours at all doses tested. AEs were typical and not dose limiting. All patients initially responded. ORR is given as 70%, and 1 of 16 patients progressed. Notably, 15/16 patients are reportedly still on treatment. A second Phase 1 study (Abstract #4397), enrolled 14 patients (mantle cell lymphoma n=7, follicular lymphoma n=3, plasmablastic DLBCL n=1, ABC-DLBCL n=1, small lymphocytic lymphoma n=1 and Waldenstrom’s macroglobulinaemia n=1) using the same dose escalation design. This is a complex and difficult group of patients. ONO-4059 induced an initial response in all patients. The ORR (all patients) = 42% and for MCL patient ORR = 50%. AEs are similar to other Btk and P13K inhibitors.

The limited available data suggest that ONO-4059 is highly potent and will be an interesting drug candidate to watch. Preclinical data show synergistic efficacy with anti-CD20 antibody Obinutuzumab/GA-101 treatment, anticipating next steps (Abstract #3069).

Gilead is bringing forward a new Syk inhibitor, now in phase 2 clinical trials. Syk is the kinase just upstream of Btk and is required for Btk activation (see the model shown in Part 1). Early Syk inhibitors from Rigel and Portola were not selective and did poorly in the clinic, as discussed previously: Gilead’s new inhibitor GS-9973 (Abstract #1634) is presented as having 7.6 nM activity against Syk with no other kinase being inhibited below 100nM. The abstract presents early activity data, with most patients responding to therapy within 4 weeks. AEs are mild except for grade 3/4 liver transaminase elevations in a small number of patients. Gilead will give a fuller picture of this phase 2 trial at the meeting. Gilead is developing GS-9973 as a single agent and also in combination with Idelalisib – the latter trial is recruiting patients with diverse types of B cell lymphomas (NCT01796470). Here again we are seeing the development of a rational combination – targeting two key elements of the signaling cascades that support lymphoma proliferation and survival.

Certainly there appears to be room for the development of additional BTK inhibitors, as this space is hardly crowded, and it will be important for companies to control their own compounds, for use in combination studies.

New PI3K inhibitors will report data at ASH, with IPI-145 from Infinity Pharmaceuticals updating a Phase 1 trial in B cell lymphomas, including rrCLL. IPI-145 is a potent PI3Kgamma/delta inhibitor, and impacts signaling through both of these isoforms at a sub-nM KD. The Abstract #677 reveals a maximum tolerated dose of 75 mg bid and also suggests that 25 mg bid is sufficient for target coverage by PK/PD analyses. The PK/PD analysis is shown in abstract #1633. These are the data that support the dosing regimen used in the ongoing Phase 3 clinical trials. The preliminary ORR for the rrCLL patients in the Phase 1 trial (19 patients) = 53%, and it appears there were a high number of discontinuations. Importantly, AEs appear to be in line with other drugs in this class. At the meeting, Infinity will present updates data from treatment-naïve CLL patients who received IPI-145 at 25 mg bid and R/R CLL patients who received IPI-145 at 25 or 75 mg bid.

Amgen is developing AMG 319, a selective PI3Kdelta inhibitor. Results from the Phase 1 dose escalation trial are shown in Abstract #678. Doses were 25 – 400 mg qd. AEs were diverse and included colitis in some patients at the 400mg dose. Ex vivo analysis of the phosphorylation of AKT (downstream of PI3K) showed nearly 100% inhibition 24 hours after dosing at 400 mg. Clinical activity was seen in all patients at all doses, with dose dependent activity observed.

Gilead has a 2nd generation PI3Kd inhibitor in clinical development, GS-9820. In Abstract #2881 dose escalation results from the Phase 1b trial are shown for doses ranging from 50 – 400 mg bid. No MTD was observed, there was no liver toxicity and 9/12 patients showed some response to therapy.

Bayer has a very interesting presentation of phase 2 data with BAY 80-6946, a selective PI3Kalpha/delta inhibitor. This drug is given IV at 0.8 mg/kg. There are notable toxicities (neutropenia, hyperglycemia, hypertension) but the efficacy is impressive at least at this early stage of development. I calculated %ORR and %CR by B cell lymphoma type, as follows (note that the sample sizes are small):

The hypertension AE is being studied in a sub-study of the ongoing Phase 2 trial (NCT01660451).

TG Therapeutics will show early data for TGR-1202 a novel orally available PI3Kdelta inhibitor. Patients have been dosed from 50 – 400 mg qd. DLT was not observed and at the 200 mg dose about half the patients had stable disease and half had progressed. The company plans to present updated results at the meeting.

Sanofi will present phase 2 results of its pan-PI3K inhibitor SAR245409, using the MTD as defined in solid tumor studies. This drug also targets the downstream signaling proteins mTORC1 and mTORC2. Data are presented in Abstract #4170. Focusing just on the CLL patients (n=10) 5 patients have SD, PFS ~ 6 months and 5 patients have a PR, PFS ~ 16.5 months.  That’s not a bad result, except that AEs are notable – all patients have cytopenias, GI complications, and hypotension. An update will be presented at the meeting. Follicular lymphoma (FL) patient data from the same trial is shown in Abstract #86. rrFL patients were given SAR245409 at 50 mg bid until disease progression (PD) or withdrawal. 36% of patients were lost to PD and 7% to AEs. 24 patients were available for evaluation, as they had responses as follows: ORR = 50%, PR = 36%, CR = 7%. For those 28 patients PFS had not been reached at 8 months.

As we can see from this Sanofi drug, moving to a pan-inhibitor and also moving further down the signaling pathways (mTORC1/2) doesn’t necessarily translate to better mono-therapeutic efficacy.

A different approach is seen with the Merck drug MK2206, an allosteric AKT inhibitor. Abstract #2882 presents a very interesting Phase 1 study. There is a 1 week “run-in” with MK2206 alone, sufficient to demonstrate a PD effect. After the first week, MK2206 is given along with bendamustine (B) and Rituxan (R). The MTD is shown to be 90 mg/week. Early results show an ORR = 89% and CR = 22% in the small Phase 1 study (n=9). These results compare favorably to BR alone (9% CR and 59% ORR) in rrCLL patients.

Other PI3K, AKT, mTOR and related drugs are in the pipeline for hematologic malignancies, and this is an area that should evolve quickly.

Next we will look at few promising pathways and drugs, coming up in Part 4.