Category Archives: Drugs (generic and brand names)

Gilead and the silly spat over Solvadi pricing

Dear readers and clients of sugarconebiotech.com,

Sunday’s NY Times did us the favor of moving the discussion about Sovaldi from treatment of HCV to HCV cure (nyti.ms/1tHcFIw). It’s about time…

We present a compelling report from Dr. Paul De Santis on the valuation and future of Gilead Sciences (GILD): Alpha BioPharma Evidence-Driven Rebuttal to Morgan and Goldman, Summary & Marketing Report.

On the heals of their impressive quarterly earnings and heading toward a transformative year, Gilead faces fundamental issues. Dr. De Santis uses comprehensive and relentless analysis, deeply vetted, to trace the paths Gilead may take, and argues that bearish analyses from Morgan Stanley, Goldman Sachs and others have led the Street to fundamentally undervalue this innovative, aggressive and ultimately triumphant company.

In the full report Dr. De Santis covers critical topics including

      M&A:  GILD will have the capacity to repurchase their entire market cap by 2020.

      HCV PRICING: Sovaldi pricing pressure will ease as the discussion shifts to cost per cure, not cost per treatment. Further, the emerging HCV competition (MRK, BMY, ABBV) has little incentive to discount price – consensus forecastsrely on premium pricing.

      HCV, EMERGING MARKETS: Sovaldi has first mover advantage in 26 Emerging Markets. The pricing model/methodology presented in this report was confirmed by GILD management – no sell-side firm has put together such a comprehensive model on E.M. 

      PIPELINE: Gilead will leverage $100B in FCF to accelerate their transformation into a premier Oncology franchise

      SUSTAINABILITY: As we’ve seen in other chronic diseases (MS, RA) the arrival of transformative therapies will drive market expansion over many years

If you maintain or trade positions in GILD, it’s competitors, partners or takeover targets I kindly suggest you acquire his detailed 145 page report. Pricing and download information are available directly from Dr. De Santis at drpauldesantis@alphabiopharmaadvisers.com. In addition to the report Dr. De Santis will send you real-time updates from the critical upcoming medical conferences (ASH, the AASLD Liver conference, CHEST, and ESMO) and important updates related to GILD and its’ competition through year-end.

We support this report based on the very high quality and content and our respect for the work of Dr. De Santis and his firm AlphaBioPharma.

To be fair, we are also long GILD.

Biogen Idec, multiple sclerosis, and the anti-Lingo story

It’s AAN conference week, and we were looking around, trying to get caught up on multiple sclerosis after a few months dedicated to oncology. We stumbled across this analyst report, and just had to comment.

Credit Suisse (CS) recently released a deep-dive report on Biogen Idec’s (Nasdaq: BIIB) anti-Lingo antibody program, assigning between $5-10BB (billion) USD of the total relapsing/remitting Multiple Sclerosis (rrMS) market share to the program by 2020. The program is currently in Phase 2. This analysis, in part, supports CS’s current price target for BIIB stock at $400, leveraging presumed growth due to the view on continued success of the anti-Lingo program. In other words, positive news on this program will help support inflated multiples through 2018, when pivotal trials may actually read out. The analysis seems ill considered, misses key aspects of BIIB corporate strategy, and places undo pressure on an early Phase 2 program. Further, intense focus on the anti-Lingo antibody program in turn places pressure on two early phase clinical trials, one due to read out in 2H14. The implication is that the base case for the price target could be undermined if the very early clinical development of the anti-Lingo program falters. That’s an unfair burden for a single high-risk program to bear.

Let’s dive in. Our focus will be on the science, but we’ll first set the stage. Our driving goal when looking at any biotech company or program is to bet the science, not the hype.

Two years ago the company set an internal goal of “400 in 5″, essentially promising to drive EPS in support of a sustained stock price of $400 USD by 2017. They came close during the biotech bubble that burst earlier this year. The stock is holding its’ own at around $320 USD. The “400 in 5″ goal is in place irrespective of the success or failure of the anti-Lingo program, which cannot read out pivotal clinical trials until at least mid-2018. With that in mind we can deconstruct the CS analysis, and create our own. Importantly, our analysis drastically de-risks the impact of the anti-Lingo program on the trajectory of BIIB growth, while leaving room for very attractive upside if this program hits.

The CS analysis correctly estimates that oral MS drugs will take over an increasing % of market share running from 2014 through 2020. No argument there, and BIIB will take the bulk of this market with Tecfidera, per multiple analysts. But CS believes that the “pipeline focus” is on the anti-Lingo antibody program to will help drive the stock price as the program matures. A few comments:

1) Analyst and/or investor focus on the anti-Lingo program is a sign of pipeline weakness, not strength. Where, one might ask, is the rest of the pipeline?

2) The program is very high-risk (and thus high return) for multiple reasons beyond the inherent weakness of being in Phase 2.

3) Management recognizes the oversized risk of the program, and will not tether stock performance to this program, instead they will act to de-risk the pipeline and performance.

Let’s look at these points one by one. First, the portfolio and pipeline. We agree that top-line growth will continue to be robust, driven by Tecfidera in the expanding orals segment of the market. We believe that the Daclizumab program is likely to succeed (the data being shown at AAN this week is very good) but it seems likely that this drug will compete for the declining injectable biologics market share with Tysabri. Maybe not, if it is successfully positioned for JC virus antibody positive patients, and can hold off the orals. Ocrelizumab may successfully evolve into the successor for Rituxan, an anti-CD20 antibody pulled from the MS market by Genentech/Roche because of exposure to generics competition. STX-100, an excellent program for fibrosis, is emerging into a rapidly evolving IPF treatment landscape (pirfenidone, nintedanib), and we’ll see if the company can eventually steer this drug into other indications, such as systemic sclerosis. The hemophilia biologics Eloctate and Alprolix are approved and launch-ready, with a consensus view that these will pull in 500MM over the first full year of sales, rising to 1BB by 2018. That’s already baked into the current forecasts.  The rest of the programs are as high risk as the anti-Lingo program, so let’s be conservative and assume half or more of these programs eventually fail. Point #2 is that the anti-Lingo program is high risk and can fail for a variety of reasons. At least three can be articulated. First, the therapeutic hypothesis, that axonal regeneration can be induced by a therapeutic in the setting of MS, has never been demonstrated. So there is an inherent biology risk. Second, the preclinical data package supports the hypothesis that blocking Lingo will improve myelin sheath regeneration and axonal function after insult or injury. However the preclinical package using MS animal models is very weak. Finally, the technical hypothesis, that sufficient quantity of antibody can be delivered across the blood-brain barrier in a robust and reproducible manner, patient to patient, has not been demonstrated. So there is an inherent technical risk. It’s also critical to note that the optic neuritis trial, the first Phase 2 to read out, perhaps addresses the therapeutic hypothesis (we could debate this, but won’t) but simply fails to address the technical hypothesis. Focusing investor attention on a Phase 2 readout in optic neuritis as a surrogate for efficacy in MS is a shell game that will go bad quickly if that Phase 2 trials comes in with negative results.

So we agree with CS that anti-Lingo antibody might work in rrMS, and it might not. We disagree that this program should be the focus of interest in the pipeline. We disagree outright with a few of their more outlandish predictions, including the statement that anti-Lingo “has potential in SPMS” the progressive and untreated form of the disease. There is no support for this statement. And while we agree that anti-Lingo is likely to be used in combination with other BIIB MS drugs, trials supporting such use are a very long way away. There is no basis to evaluate such a statement at this time. Finally, instead of concluding that pipeline focus on the anti-Lingo program is a positive, as CS does, we see this as a sign of a fundamentally weak BIIB pipeline.

Should we be surprised? Let’s consider that BIIB has not successfully developed a novel internal program since Avonex and Amevive, well over 15 years ago (yes there is Peligry, but that’s just pegylated-interferon, still, they did develop it). What else? Rituxan came from Idec. Tysabri came from Elan. Tecfidera came from Fumapharm. Daclizumab came from PDL Biopharma/Abbvie. Ocrelizumab came from Genentech/Roche. Long acting Factors XIII and XI came from Syntonix Pharmaceuticals. STX-100 is a BIIB moelcule but had to leave for 5 years in order to be successfully developed by Stromedix. In the meantime the Immunology Department has produced no drugs since it’s inception in the mid-80s, well over 20 years ago. The oncology experiment (BIIB San Diego) produced no drugs. The BIIB hemophilia group will produce no new drugs (more on this below). The medicinal chemistry effort has produced no drugs (although we think they will). The BIIB neurology research group has produced no drugs outside of the interferon space, although they are getting closer (anti-Lingo, BIIB037). So why is this company even competitive, indeed dominant, in MS?

The answer is simple and compelling. BIIB excels in the development of in-licensed, clinical stage MS programs. Look at what they’ve brought in and then brought to registration: Tysabri is the single best MS drug available (nothing else is even close); Tecfidera is the single best oral MS drug, and again it’s not even close; Daclizumab will present an extraordinary efficacy/safety profile, and so on. Let’s also consider that while BIIB was accumulating and developing these assets, their competition was developing cladribine, alemtuzumab (campath), lemtrada, aubagio and other hideous potions. Even Novartis came razor close to missing with Gilenya, a nicely efficacious drug that has a challenging toxicity history

Perhaps anti-Lingo antibody will join the BIIB parade of success in MS, but company management is not counting on it. When management set a goal of “400 in 5″ in 2012, they meant it, which means they cannot wait for anti-Lingo or any other early Phase 2 program to mature. This is our final point from above, that management will de-risk the pipeline. This means they have 2 choices, and they have been excellent at executing on either or both of these choices:

1) Buy a late clinical stage MS asset/company.

2) Cut costs in order to manage EPS aggressively.

A third possible outcome of course is that they will do both. A very interesting question is: what attractive MS asset/company could BIIB buy? There are some very compelling answers, and maybe we’ll share these, but not today. A less interesting question, because the answer is so obvious, is where to cut. Let’s go back to those hemophilia drugs, brought in on a wave of enthusiasm for the much broader hematology space. What happened? When costs needed to be trimmed a “strategic review” quickly revealed that hematology was not so attractive after all. So the hemophilia R&D group was slashed, and only the clinical programs retained. Note further that those Factor XIII and Factor XI drugs are utlilizing very valuable and expensive bio-manufacturing capacity for the company. What might happen here? BIIB could sell the programs for 10-20x annual sales to Bayer or Novo Nordisk and keep the manufacturing rights for 5 years or more. We’re just guessing, but we also think it’s a very good bet.

The other obvious target is the Immunology group. A possible hint here is that a new department has been formed, carrying the name Remodeling and Repair or something similar. The department is built around the very interesting Phase 2 fibrosis program STX-100, mentioned above. A simple decision would be to move the few Immunology clinical assets (the anti-TWEAK and anti-CD40L antibodies) under this new department, and jettison the Immunology Research efforts. Such a move would mimic what was done in the hematology space, and would further move the company further away from basic Research, which historically has failed to move therapeutics forward, and further toward Development: in-licensing, clinical execution, regulatory execution and bio-manufacturing, the company’s true core competencies.

Will BIIB do any of these things? We have no idea. But we have watched this company for a long time, and if top-line results fail to drive EPS to the goals promised, the company will act decisively to control the bottom line. Personally, we expect to see an acquisition in short order, rather than further cuts. Just to reinforce what we said at the beginning: the proposed corporate strategy fundamentally de-risks the impact on the anti-Lingo program on the company fortunes, leaving intact the potential for a large upside if that program performs well in the clinic.

disclosures: PDR was a senior member of BIIB’s Immunology department for a long time, and retains both positive and negative biases. PDR is also long BIIB stock.

stay tuned

Three high-altitude take aways from AACR14

The American Association for Cancer Research (AACR) 2014 meeting last week was high energy and high impact. We will dive into particular talks and specific pathways and indications in later posts, in the meantime I wanted to mention a few key themes.

1) Immunotherapy Versus The World.  That’s a deliberate overstatement of a subtle shift in emphasis from last year’s big meetings, where combinations of immunotherapy with just about anything else were the hot topic. This year there were several talks which emphasized the futility of chasing oncogenic pathways and all of their resistance mutations, one after the other, as opposed to letting the immune system do the work. However, it seems to me overly optimistic to believe that immune modulation can defeat a high percentage of patient  tumors on its own, as some speakers acknowledged. Combinations remain necessary although we will have to work past some notable failures in combo trials, such as the liver toxicity seen in the ipilimumab + vemurafenib combination phase 1, discussed briefly by Antonio Ribas               (see http://www.nejm.org/doi/full/10.1056/NEJMc1302338).

2) Immunotherapy Versus Itself.  In the ultimate battle of the titans, we see different immunotherapeutic modalities squaring off. This is a theme we’ve touched on before in this space, but the  competition is getting heated. In some indications, the leukemias, lymphomas, perhaps melanoma and some other solid tumors, there is an abundance of therapeutic choices, and the hard question of which therapy best suits which patient will ultimately need to be addressed outside of the context of clinical trial enrollment. Several talks really brought this message home. Roger Perlmutter of Merck (and before that, Amgen) envisions an important role for multiple immune therapies including bi-specific antibodies, chimeric antigen receptors (CARs), and immune checkpoint modulators like Merck’s anti-PD-1 antibody MK-3475.  For B cell lymphoma for example, there is blintumumab (Amgen), a potent bi-specific that redirects T cells to CD19+ tumor cells (and normal B cells), and there is CTL019, a CAR therapeutic which does much the same thing. The therapeutic profiles and toxicity differ, but the general idea is the same. One big difference is that while CTL019 drives T cell expansion and the development of long term anti-tumor memory, the bi-specific does not. Which is better? We don’t know yet. He did not mention that one might do well trying a course of BTK inhibition plus anti-CD20 antibody therapy, perhaps with restricted chemotherapy first e.g ibrutinib plus rituximab and chemo (R-BR or R-F). That choice comes down to efficacy, then toxicity, and eventually cost. Efficacy seems to be a home run with the CAR therapeutics, although these may run into trouble in the area of toxicity and cost calculation. Renier Brentjens discussed the CAR therapies being developed under the Juno Therapeutics umbrella. Acute lymphoid leukemia (ALL) can be treated with CAR 19-28z modified T cells to achieve a >80% complete response rate with >70% of patients showing no minimal residual disease, an outstanding result. However, 30% of treated patients end up in the ICU due to cytokine release syndrome and other toxicity, and recently patients in the ALL trials have died from unanticipated tox causes. Juno stopped 5 trials of their CAR technology last week due to toxicity. Apparently one patient died of cardiovascular complications and another of CNS complications (severe uncontrolled seizures) – it was hard to nail down as Dr Brentjens had gone off his prepared talk for these remarks which were off the cuff, so comment please if you have better info on this. Carl June discussed Dr Brentjens’ presentation, noting that the clinical results were really quite striking, and contrasting the CD28 motif-based CARs with the 4-1BB-based CARs (as designed by Dr June with U Penn and licensed to Novartis). He also stressed that in chronic lymphocytic leukemia (CLL) they have had patients who have failed up to 10 prior therapies, including rituximab and/or ibrutinib, and these patients have responded to CAR treatment. That’s very impressive data. The roadblocks to widespread use of CAR therapy however are large and include the toxicity, the “boutique” nature of the current protocols, the cost. Perhaps, Dr June suggested, CAR will end up as third line therapy, reserved for salvage therapy. I for one hope not.

Also in the immunotherapy space were hot new targets (e.g. CD47, OX40, GITR), advances on the vaccine front, and a few surprises. We’ll update soon.

3) The Medicinal Chemists Have Been Busy.  Not to be drowned out by the Immunotherapy tidal wave, small molecule therapies targeting specific oncogenic pathways continue to be developed and show promise. Most readers will be aware of the high stakes showdown (so billed) between Novartis, Pfizer and Lilly in the field of specific CDK4/6 inhibitors – in addition to bringing forward some really nice phase 2 data (we’ll discuss these another time) this “showdown” also illustrates that current portfolio strategy drives a lot of overlapping effort by different companies. As expected, much of the action is moving downstream in the signaling pathways, so we saw some data on MEK1 inhibitors and ERK1/2 inhibition. There were some new BTK inhibitors, nice advances in the epigenetics space, and some novel PI3K inhibitors. All grist for the mill.

stay tuned.

ANTICIPATING NEW THERAPEUTICS AND FORECASTING TREATMENT TRENDS FOR ACUTE MYELOID LEUKEMIA – PART 1

 by Paul D Rennert, February 11, 2014

In looking at Acute Myeloid Leukemia (AML) we see a cancer field right on the cusp of change in clinical practice. Standard of care chemotherapy regimens and stem cell transplantation protocols have proven to be of limited utility, especially in older patients. However, potentially big advances in care are being made, with exciting news coming out regularly. As we move toward the spring Medical Conference season, we felt an overview of this rapidly evolving area of oncology would be timely.

AML is a rapidly growing cancer of myeloid lineage cells that proliferate in the bone marrow and interfere with normal hematopoiesis. AML typically arises in the context of defined genetic mutations. For example, translocations of chromosome 16 disrupt RUNX1 gene activity and are one of the several underlying causes of Core Binding Factor AML. CBF-AML). Since RUNX1 regulates the transcription of many genes, the effect of its disruption is complex. CBF-AML patients are generally responsive to chemotherapy initially, although up to half of these patients will relapse over time due to additional genetic mutations.

Mutation of the FLT3 protein is the most common genetic abnormality in AML, found in about 30% of patients. This is a genetic characteristic associated with poor prognosis. The most common FLT3 mutation, FLT3-ILD, is caused by an tandem duplication within the coding region of the gene. The resulting protein drives hyper-signaling and oncogenic cell responses. Mutations that change the active site of the protein, causing unregulated phosphorylation, have also been described. Mutations in the receptor tyrosine kinase c-Kit are also associated with oncogenic signaling in AML. Both of these pathways cause mutiple downstream effector pathways to be activated. The JAK2 mutations, commonly see in myelofibrosis and other myeloproliferative disorders, are rare in AML but when characterized can potentially be treated with Jak2 inhibitors.

According to a recent market research analysis                           (http://www.transparencymarketresearch.com/acute-myeloid-leukemia-therapeutics-market.html) a total of 62,226 new cases of Acute Myeloid Leukemia (AML) were recorded in 2010, with 95,000 predicted new cases for 2015 and nearly 130,000 predicted new cases in 2020. Note that as of February 2014 approved agents for AML remain limited to chemotherapeutics (http://www.cancer.gov/cancertopics/druginfo/leukemia#dal2). Despite the lack of new targeted drugs, the AML therapeutics market was nearly 240 MM USD in 2011. At the current rate of growth the AML market could reach over 700 MM USD by 2018. These numbers are based on the analysis of future AML drugs growing at a 17% compound annual growth rate from through 2018.

Numbers like these are continuing to drive intensive research into effective, novel therapies for AML. It only helps that in many cases such therapeutics find use in other hematopoietic diseases such as Chronic Myeloid Leukemia (CML) and in the B cell lymphomas, including Hodgkin’s Lymphoma and the non-Hodgkin’s Lymphomas (NHL).

 There is obvious unmet medical need for effective therapies in AML since this is a disease characterized by quick relapse after therapy with grim survival statistics. In some older patients, survival is as little as 1-1.5 years despite first and second line treatment regimens.

What’s exciting from the drug development and biotech investment perspectives is that the AML treatment landscape is advancing simultaneously across therapeutic modalities. This rapidly changing landscape give us a chance to look at targeted small molecule drugs, monoclonal antibodies (naked, bi-specific, radiolabelled, immunotherapeutic, ADC), targeted T cells and other novel technologies.

 We can then ask ourselves: who will the winners be in 5 years?

 A) Targeted small molecule drugs.

Lets just be clear upfront that the goal of these targeted therapies is to get patients who have relapsed, or are refractory to chemotherapy, to a complete response (CR) with minimal residual disease (MRD) so they can qualify for an allogeneic stem cell transplant (SCT). That’s a lot of acronyms but what this is really saying is that for most patients the goal is a modest one – we are not asking for a durable remission, at least not yet.

 A variety of established drugs are being tested in AML. Also, the identification of oncogenic mutations in FLT3 and cKIT has driven interest in developing new tyrosine kinases inhibitors (TKIs) for AML.

 Sorafenib (NexavarTM; Bayer and Onyx) is a dual targeting drug that blocks RAF signaling (and therefore the MEK>ERK signaling) and also the growth factor receptor tyrosine kinases VEGFR and PDGFR. The NCI is running a large phase 3 trial enrolling new onset pediatric AML patients (NCT01371981) with sorafenib being given in combination with various chemo regimens.  Bayer and Onyx are running several earlier phase AML trials. An interesting phase 1 trial in patients 18 or older combines sorafenib with plerixafor and G-CSF (NCT00943943). The idea here is to have the CXCR4 blocker (plerixafor) and the growth factor (G-CSF) flush tumor cells, and also tumor stem cells, from the bone marrow and lymph nodes so that they are more sensitive to sorafenib treatment. This trial is co-sponsored by Genzyme/Sanofi, which owns plerixafor.

Another interesting trial is the Phase 1/2 study of the combination of sorafenib, with vorinostat, and bortezomib (NCT01534260). Here we have a proteasome inhibitor and an HDAC inhibitor added to growth factor and signaling inhibition provided by sorafenib. This potent combination is being used in patients with a poor genetic risk profile, including FLT3-ILD positive tumors. This study is co-sponsored by Bayer/Onyx, Millennium/Takeda and Merck Sharp & Dohme Corp.

Bristol Myers Squibb is running an interesting trial (NCT01620216) in which AML and acute lymphocytic leukemia (ALL) patient samples are analyzed for sensitivity to drug treatment ex vivo, after a period on drug in the trial, as follows:

“An in vitro kinase inhibitor assay will be used to determine the sensitivity of primary leukemic cells to four kinase inhibitors/drugs:

Drug: Sunitinib, 50 milligrams (mg) qd, with or without food, for 4 weeks

Drug: Dasatinib, 100 mg qd…possible escalation to 140 mg qd for 28 days

Drug: Nilotinib, 400 mg twice daily for 28 days

Drug: Sorafenib, 400 mg (2 tablets) orally twice daily without food for 28 days

Drug: Ponatinib, 45 mg dose once per day

Sunitinib (Sutenttm; Pfizer) makes sense as a pan-growth factor receptor inhibitor; dasatinib (Spryceltm; Bristol Myers Squibb) is a Src and c-Kit inhibitor and is a reasonable choice for AML; nilotinib (Tasignatm; Novartis) is a pretty specific Bcr-Abl kinase inhibitor and is probably only being used for the ALL population – and even there only 25% of ALL patients carry this translocation; sorafenib we discussed earlier; ponatinib (Iclusigtm; Ariad) has a grab bag reactivity profile, hitting the BCL-ABL kinase, FLT3, RET, c-KIT and the FGFR, PDGFR and VEGFR growth factor receptor kinases. This is a dangerous drug, with a very narrow FDA approval in CML, and I suspect enrollment in this little exploratory trial will be stopped if possible.

If I had to guess I would say that this rather odd trial design has several goals. One is to look for signs of efficacy, although a month is pretty short duration. One might also look for patterns of resistance to therapy, which would be very interesting. Since this is BMY, I’d be surprised if they weren’t also looking at cell surface markers for possible immunotherapy treatment – more on this subject later.

Results from a dasatinib trial in CBF-AML were recently presented at the American Society of Hematology (ASH) conference (Abstract #357). Dasatinib was added to induction and consolidation chemotherapy in newly diagnosed AML patients. Unlike the rrAML population, the CBF-AML population can experience sustained periods of remission prior to relapsing, especially in younger patients. Since some of the relapses are driven by gain of function mutations in c-Kit, dasatinib should prevent at least those clones from becoming established. Early results looked good but longer term data are needed to see if this regimen will remain effective.

Imatinib (Gleevectm; Novartis) another Bcr-Abl, c-Kit and PDGF-R inhibitor, has been tested in multiple AML trials, but the results have not led to approval for use in AML. An interesting trial of the cytotoxic/immunomodulatory agent lenolidomide (Revlimidtm; Celgene) plus chemotherapy is being run by the NCI (NCT01246622). Lenolidomide has been approved for the treatment of a different bone marrow resident cancer, multiple myeloma (MM).

Anyway there is a lot of similar clinical trial work being done – using approved drugs in this new indication and looking for efficacy. This is ultimately good both for patients and the drug development companies.

Lets move on to some newer drugs in the pipeline. The FLT3 inhibitors give us a sense of the difficulty here, with low response rates as monotherapies.

Quizartinib (Ambit Biosciences; AMBI) remains stuck between phase 2 and 3 for relapsed/refractory (rr) AML. This drug is a FLT3 inhibitor with a somewhat tortured history, having been partnered for a time with Astellas, then returned, then running nicely in the clinic before running into disagreement with the FDA over approvable endpoints and safe dosage. In early December the company announced it would have to run a phase 3, likely with lower starting doses, in order to obtain FDA approval. Investors were hoping the company could file on its phase 2 trials. Notably, later in December Ambit showcased its’ quizartinib data from the FLT3-ILD rrAML trial, in which a 50% response rate (50% or greater reduction in leukemic blast cells) was reported with relatively low doses of drug. Unfortunately, it will be a while yet before more news becomes available about this drug.

In the meantime heavy hitter Novartis is already in phase 3 with its’ FLT3 and Protein Kinase C inhibitor midostaurin. The phase 3 in newly diagnosed patients is being run by the NCI (our tax dollars at work), along with The Alliance for Clinical Trials in Oncology and the Cancer and Leukemia Group (NCT00651261). A trial of midostaurin administered with or without bortezomib in adult rrAML patients is being run by Novartis and Millennium/Takeda (NCT01174888). Preliminary results were presented at ASH (abstract #3966). While response rates were impressive the toxicity was extreme, and this seemed to be due to the bortezomib dose, which was adjusted. Phase 2 trials in adult patients who carry c-KIt, FLT3-ILD, and various other mutation or cytogenetic markers are also underway (NCT01830361, NCT01846624). A phase 2b midostaurin  monotherapy study published several years ago showed modest improvement in AML patients with mutated FLT3; this study recognized the need for combination therapy to improve the clinical response (http://www.ncbi.nlm.nih.gov/pubmed/20733134).

Another FLT3 inhibitor, lestaurtinib, is the subject of 2 NCI sponsored trials in pediatric ALL/AML but drug development of this agent seems to have stalled when Teva bought Cephalon. Another FLT3 inhibitor is PLX3397 (Plexxikon) which has activity against  KIT, CSF1R and FLT3. This drug is in a phase 1/2 trial in adult rrAML (NCT01349049).

One of the major challenges for FLT3 inhibitors is breadth of action. These inhibitors work best on patients who have mutated FLT3 and are less effective in patients with normal FLT3. Also, secondary mutations have already been discovered in response to FLT3 inhibition. Specifically, in those patients who have mutations in the active site of the kinase, so-called gatekeeper mutations arise, conferring resistance to the drug.

A dominant theme in recent drug development for AML has been built on the observation that proteasome inhibitors can impact cancers of the bone marrow. Disruption of proteasome activity blocks a wide spectrum of cellular activities, and is particularly effective against rapidly dividing cells (like leukemic blasts) but also relatively quiescent tumor stem cells, that require specific proteasome-dependent signaling pathways (e.g. NK-kB). Bortezomib (Velcadetm, Millennium/Takeda) has shown activity in older patients when combined with chemotherapy. A phase 3 combination trial with sorafenib in newly diagnosed AML patients is underway, sponsored by the NCI (NCT01371981).

Carfilzomib (Onyx Pharmaceuticals) is in an early stage trial for AML, along with extensive trials in MM, B cell lymphomas, etc. The drug is furthest along in MM, now in phase 3 (NCT01568866). Early reports so far have suggested that this drug has an activity profile similar to bortezomib, but may have a better safety profile. This is an interesting drug (and company) to watch. They have a second generation oral version of carfilizomib, oprozomib, in phase 1 MM trials. Millennium/Takeda are developing ixazomib in MM and lymphomas. An AML trial is listed but not yet recruiting.

A third theme that we can follow in AML therapeutic drug development is the use of drugs that impact epigenetic gene regulation. Because AML is driven by genetic translocations, gene regulation at the level of chromatin structure is disrupted. There are two processes at work here that can be targeted. One is the aberrant methylation of CpG islands in gene promoter regions, which can be targeted by DNA methyltransferase inhibitors. The second is changes in the conformation of chromatin caused by dysregulated histone acetylation. This process can be therapeutically targeted using histone deacetylase [HDAC] inhibitors.

The HDAC inhibitor vorinostat (Zolinzatm, Merck) has been extensively studied in AML, and is currently in a phase 3 trial with chemotherapy for young patients with newly diagnosed disease (NCI; NCT01802333). Vorinostat monotherapy was generally ineffective, but combination with chemo agents proved much more potent. As detailed at ASH in December (Abstract #2684), newly diagnosed and rrAML patients were enrolled in a phase 2 expansion study. Of 75 patients, 57 patients achieved CR, and 7 achieved CR with incomplete platelet recovery (CRp), for an overall response rate of 85 percent. Median overall survival was 82 weeks and median event free survival was 47 weeks. For patients with the high-risk Flt-3 ITD mutation the 10/11 achieved CR and 1/11 CRp. The ORR = 100% in these patients. Their median overall survival was 91 weeks and median event free survival was 66 weeks. About 25% of the total patients in CR received SCT.

Other combination trials include the sorafenib trial mentioned above, and a trial in combination with antibody therapy (gemtuzumab ozogamicin) for rrAML (NCI; NCT00895934). This trial reported early results at ASH (Abstract #3936). The response rates ere encouraging and about 20% of patients obtained durable remission. There were significant toxicity issues. This drug is very likely to play a critical role in the evolution of combination therapy for AML. We’ll discuss antibody therapies further in Part 2.

Other important HDAC inhibitors in development for AML is panobinostat (Novartis). What’s interesting about the development campaign with this drug is the pairing in multiple trials with 5-azacitidine, a DNA methytransferase inhibitor. In such settings two modes of epigenetic regulation are being targeted simultaneously. One of these studies published findings last month                                 (http://www.nature.com/bcj/journal/v4/n1/full/bcj201368a.html) and demonstrated good tolerability and reasonable response rates. Clearly, this combination should move forward in the context of chemotherapy or other drugs. Of note the DNA methyltransferase inhibitor decitabine (Dacogentm, MGI Pharma) is already approved for AML. There was also a presentation on the HDAC inhibitor entinostat (Syndax Inc) with 5-azacitidine in myeloid neoplasia (Abstract #2777), and there are several clinical trials listed for AML, however this drug is mainly being used in solid tumor trials.

Other interesting drugs in this area include alisertib, an Aurora A kinase inhibitor (Millennium/Takeda) being tested extensively in B and T cell lymphomas and in solid tumors. There are several AML trials including a phase 2 trial completed by MLMN (NCT00830518). Selinexor, (Karyopharm) a selective inhibitor of nuclear export, in in phase 1 trial for advanced AML. Abbvie’s Bcl2 inhibitor ABT-199 is also in an AML trial.

If we take a step back we can appreciate that in small molecule development Novartis, Merck and Onyx are placing big bets in this therapeutic area. We’ll sort out the best looking therapeutics as we dig in a little deeper.

In Part 2 we’ll take a look at the biologics landscape, and begin to draw the bigger picture.

Alemtuzumab and MS – Just The Facts

Lemtrada For Multiple Sclerosis – Just The Facts

The debate over the FDA’s reluctance to approve alemtuzumab (brand name Lemtrada, an anti-CD52 antibody, aka Campath) continues, with heated opinions being expressed, mainly by those that want Lemtrada approved. We note without comment that a fair number of the FDA’s fiercest critics have exposure to stock warrants tied to this drug’s commercial success. The FDA stance seems to some to be overly tough, particularly as the drug has been approved for MS in other markets, notably the often risk-adverse EU.

I’ve been puzzled by this debate, and more puzzled since it is taken place more of less without discussion of the Phase 3 clinical trial data. Granted this is hard for some of us to get. I do not have the FDA documents for example. The clinical trial data is behind a paywall at the Lancet, and I’m just annoyed enough at the price to resist paying it. So let’s see what we can do using just publicly available information.

The Lancet summaries are available. Here is the first one (via http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61769-3/abstract):

Background

The anti-CD52 monoclonal antibody alemtuzumab reduced disease activity in a phase 2 trial of previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of first-line alemtuzumab compared with interferon beta 1a in a phase 3 trial.

Methods

In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18—50 years with previously untreated relapsing-remitting multiple sclerosis. Eligible participants were randomly allocated in a 2:1 ratio by an interactive voice response system, stratified by site, to receive intravenous alemtuzumab 12 mg per day or subcutaneous interferon beta 1a 44 μg. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and once per day for 3 days at 12 months. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00530348.

Findings

187 (96%) of 195 patients randomly allocated interferon beta 1a and 376 (97%) of 386 patients randomly allocated alemtuzumab were included in the primary analyses. 75 (40%) patients in the interferon beta 1a group relapsed (122 events) compared with 82 (22%) patients in the alemtuzumab group (119 events; rate ratio 0·45 [95% CI 0·32—0·63]; p<0.0001), corresponding to a 54·9% improvement with alemtuzumab. Based on Kaplan-Meier estimates, 59% of patients in the interferon beta 1a group were relapse-free at 2 years compared with 78% of patients in the alemtuzumab group (p<0·0001). 20 (11%) of patients in the interferon beta 1a group had sustained accumulation of disability compared with 30 (8%) in the alemtuzumab group (hazard ratio 0·70 [95% CI 0·40—1·23]; p=0·22). 338 (90%) of patients in the alemtuzumab group had infusion-associated reactions; 12 (3%) of which were regarded as serious. Infections, predominantly of mild or moderate severity, occurred in 253 (67%) patients treated with alemtuzumab versus 85 (45%) patients treated with interferon beta 1a. 62 (16%) patients treated with alemtuzumab had herpes infections (predominantly cutaneous) compared with three (2%) patients treated with interferon beta 1a. By 24 months, 68 (18%) patients in the alemtuzumab group had thyroid-associated adverse events compared with 12 (6%) in the interferon beta 1a group, and three (1%) had immune thrombocytopenia compared with none in the interferon beta 1a group. Two patients in the alemtuzumab group developed thyroid papillary carcinoma.

Interpretation

Alemtuzumab’s consistent safety profile and benefit in terms of reductions of relapse support its use for patients with previously untreated relapsing-remitting multiple sclerosis; however, benefit in terms of disability endpoints noted in previous trials was not observed here.

What is this telling us?

1) this is a 2-year trial in previously untreated MS patients; the dose regimen is 12 mg daily for 5 days and then at 12 months a second regimen of 12 mg daily for 3 days
2) the active comparator is Rebif, a beta-interferon
3) there was a benefit seen in relapse rate: about 20% fewer patients had a relapse in the alemtuzumab arm as compared to the Rebif arm
4) there was no improvement in time to 6-month sustained accumulation of disability
5) 90% of alemtuzumab patients had infusion reactions but only 3% on these were serious
6) Over 60% of patients experienced infections, over 60% developed cutaneous herpes, over 60% developed thyroid associated adverse events, and 1% developed immune thrombocytopenia.

Summary: alemtuzumab hit one of its primary endpoints, missed the second, and had a challenging toxicity profile.

How about that second paper in Lancet? Well, here is the abstract (via http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(12)61768-1/abstract)

Background

The anti-CD52 monoclonal antibody alemtuzumab reduces disease activity in previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of alemtuzumab compared with interferon beta 1a in patients who have relapsed despite first-line treatment.

Methods

In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18—55 years with relapsing-remitting multiple sclerosis and at least one relapse on interferon beta or glatiramer. Eligible participants were randomly allocated in a 1:2:2 ratio by an interactive voice response system, stratified by site, to receive subcutaneous interferon beta 1a 44 μg, intravenous alemtuzumab 12 mg per day, or intravenous alemtuzumab 24 mg per day. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and for 3 days at 12 months. The 24 mg per day group was discontinued to aid recruitment, but data are included for safety assessments. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability, comparing alemtuzumab 12 mg and interferon beta 1a in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00548405.

Findings

202 (87%) of 231 patients randomly allocated interferon beta 1a and 426 (98%) of 436 patients randomly allocated alemtuzumab 12 mg were included in the primary analyses. 104 (51%) patients in the interferon beta 1a group relapsed (201 events) compared with 147 (35%) patients in the alemtuzumab group (236 events; rate ratio 0·51 [95% CI 0·39—0·65]; p<0·0001), corresponding to a 49·4% improvement with alemtuzumab. 94 (47%) patients in the interferon beta 1a group were relapse-free at 2 years compared with 278 (65%) patients in the alemtuzumab group (p<0·0001). 40 (20%) patients in the interferon beta 1a group had sustained accumulation of disability compared with 54 (13%) in the alemtuzumab group (hazard ratio 0·58 [95% CI 0·38—0·87]; p=0·008), corresponding to a 42% improvement in the alemtuzumab group. For 435 patients allocated alemtuzumab 12 mg, 393 (90%) had infusion-associated reactions, 334 (77%) had infections (compared with 134 [66%] of 202 patients in the interferon beta 1a group) that were mostly mild-moderate with none fatal, 69 (16%) had thyroid disorders, and three (1%) had immune thrombocytopenia.

Interpretation

For patients with first-line treatment-refractory relapsing-remitting multiple sclerosis, alemtuzumab could be used to reduce relapse rates and sustained accumulation of disability. Suitable risk management strategies allow for early identification of alemtuzumab’s main adverse effect of secondary autoimmunity.

Again, what is this telling us?

1) this is a 2-year trial in patients with relapsing-remitting multiple sclerosis and at least one relapse on interferon beta or glatiramer; the dose regimen is 12 mg or 24 mg daily for 5 days and then at 12 months a second regimen of 12 mg or 24 mg daily for 3 days. The 24 mg dose was discontinued.
2) the active comparator was Rebif, a beta-interferon
3) there was a benefit seen in relapse rate: 16% fewer patients experienced a relapse on alemtuzumab as compared to Rebif
4) importantly, 65% of patients were relapse free at 2 years
5) there was an improvement in time to 6-month sustained accumulation of disability
6) 90% of alemtuzumab patients had infusion reactions
7) 77% of alemtuzumab patients experienced infections, 16% developed thyroid associated adverse events, and 1% developed immune thrombocytopenia.
Summary: alemtuzumab hit both of its primary endpoints and had a challenging toxicity profile.

How does this efficacy compare to other treatments? The reduction in annualized relapse rate (ARR) lies between the beta-interferons or copaxone and highly efficacious drugs like natalizumab (Tysabri), daclizumab or fingolimod (Gilenya). The following data are taken from the UPTODATE website, last updated January 15, 2014.
(http://www.uptodate.com/contents/treatment-of-relapsing-remitting-multiple-sclerosis-in-adults)

agent
trial(s)
ARR (across doses)
ARR/comparator
SAD met?
dimethyl fumarate (Tecfidera)CONFIRM24%40% (placebo)trend/ns
dimethyl fumarate (Tecfidera)DEFINE18%36% (placebo)yes
fingolimod (Gilenya)FREEDOMS17%40% (placebo)yes
fingolimod (Gilenya)TRANSFORMS18%36% (interferon beta 1-a)not assessed
alemtuzumab (Lemtrada)CARE-MS I22%40% (interferon beta 1-a)no
alemtuzumab (Lemtrada)CARE-MS II (relapsed patients)35%53% (interferon beta 1-a)yes
natalizumab (Tysabri)AFFIRM (relapsed patients)26%81% (placebo)yes
natalizumab (Tysabri)SENTINEL (relapsed patients)38%82% (placebo)yes

So it seems to me that we have an efficacy/toxicity profile on a par with fingolimod and natalizumab. Of note, the UPTODATE profile concludes the section of alemtuzumab as follows:

“Although its precise role in the management of RRMS is not yet settled, alemtuzumab will probably be used as a second-line agent for patients with RRMS who have an inadequate response to treatment with interferons and glatiramer. The role that alemtuzumab will play in the context of other newer MS disease-modifying agents (eg, fingolimod, teriflunomide, and BG-12) is still undefined. Alemtuzumab therapy requires monitoring for infusion reactions and prophylaxis for herpes virus infections and Pneumocystis jirovecii (PCP) pneumonia during treatment and for several weeks after treatment. Prolonged surveillance for bone marrow suppression, infections, and autoimmune disorders such as immune thrombocytopenia is also necessary.”

So that seems to be the heart of the problem, that the comparison to the most relevant medications is not well defined and you have a lot of toxicity that requires monitoring.

As the title said, “just the facts” – I don’t aim to draw conclusions here but just lay out the data so when we see arguments pro or con for this drug, we have a place to turn to look at the data.

The development of combination therapies for B cell lymphoma: ABT-199

The role of ABT-199 in the development of combination therapies in lymphoma.

Following yesterday’s blockbuster win for PCYC and JNJ – the Phase 3 trial versus Arezza was stopped early on clear PFS and OS benefit – it seems a little deflating to return to AbbVie, whose Bcl2 inhibitor ABT-199 has been dogged by Tumor Lysis Syndrome (TLS) problems, some fatal, and recent rumors of oversight problems at one clinical site. I stated the other day that ibrutinib would win the medical marketplace for B cell lymphoma treatment, based on its impressive suite of clinical trials, and the results announced yesterday support that opinion. I still believe that combo therapy is the critical path forward in this field, and ibrutinib and idelalisib are the clear leading candidates for combo treatment protocols.

However, ABT-199 remains a wildcard and could be transformative if developed carefully. The drug demonstrates ORR and CR responses in B cell lymphoma that are very dramatic, as detailed earlier. In the spirit of our earlier January posts, lets look at the clinical trial spectrum for ABT-199. There are five trials listed for ABT-199 monotherapy in oncology, including the phase 1 extension. These include trials in relapsed/resistant NHL, CLL, high-risk CLL (del17p), MM, and AML. The inclusion of acute myeloid leukemia (AML) distinguishes ABT-199 from the other lymphoma drugs, and is based on the mechanism of action and profiling of different tumor types for sensitivity to Bcl2 inhibition.

The combination trials are very narrow in scope and reflect the fact that the ABT-199 is partnered with Roche/Genentech, and therefore the anti-CD20 mAbs used are those developed by Roche, that is, rituximab and obinutuzumab (Gazyva). Obinutuzumab is already approved for the treatment of previously untreated CLL, i.e., as first line therapy. The obinutuzumab trial with ABT-199 is sponsored by Roche/Genentech, illustrating the depth of this collaborative effort. Roche has an ongoing preclinical BTK program, and it will be interesting to see if a combination trial with ABT-199 is eventually filed.

Here are the combination trials listed:

Trial Number
Phase
date filed
Combination
Indication
NCT0159422914/20/2012bendamustine/rituximabrrNHL and DLBCL
NCT0167190418/10/2012bendamustine/rituximabCLL (rr & untreated)
NCT016826161b6/26/2012rituximabrrCLL and SLL
NCT0168589219/12/2012ObinutuzumabCLL (rr & untreated)

The ultimate success of the program will depend in large measure on controlling the TLS issue. Its worth reminding ourselves that TLS did not suddenly become a toxicity concern in the treatment of B cell lymphoma. It occurs with anti-CD20 treatment and with chemotherapy treatment, as a result of triggering the death of a large number of tumor cells. The problem for ABBV and ABT-199 is that TLS does not seem to be related to dose given, remaining somewhat unpredictable (aside from worrying when patients present with bulky disease, which indicates huge number of tumor cells in the lymph nodes, bone marrow, etc). The recent outcry over moving one patient from one dose to another (150mg to 1200mg if I remember right) seems a little silly when a dose of 50mg can trigger TLS in a lymphoma patient. That said, the burden is on AbbVie to demonstrate that they can provide better efficacy than the competing drugs (ibrutinib and idelalisib), safely. If they can do this, I predict that ABT-199 will have a big role to play in the treatment of B cell lymphoma. If they continue to struggle then this drug will will still have a role, but may be relegated to second line or even salvage therapy status. Given the resources behind it, from both AbbVie and Roche, I imagine that a huge effort will be brought to bear on understanding and controlling the TLS toxicity.

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.

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 clinicaltrials.gov, 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:

TRIAL NUMBER
PHASE
DATE FILED
IBRUTINIB WITH
INDICATION
NCT01980654210/24/2013rituximabuntreated FL
NCT0188056726/4/2013rituximabrrMCL
NCT0152051921/25/2012rituximabhigh risk CLL, SCL
NCT0161109035/15/2012rituximab/bendamustinerrCLL, rrSCL
NCT0177684031/24/2013rituximab/bendamustineuntreated MCL
NCT01479842111/1/2011rituximab/bendamustinerr DLBCL,MCL,iNHL
NCT0185575035/14/2013R-CHOPDLBCL-ABC
NCT0188687236/24/2013noneuntreated CLL
rituximab
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:

TRIAL NUMBER
PHASE
DATE FILED
IBRUTINIB WITH
INDICATION
NCT020131281,212/11/2013ublituximabCLL, MCL
NCT0157870734/11/2012v ofatumumabrrCLL
NCT012177491,210/7/2010ofatumumabCLL
NCT01478581211/18/2011nonerrMM
NCT0184172321/24/2013noner Hairy Cell leukemia
NCT019627921,29/27/2013carfilzomibMM

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.

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 clintrials.gov 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.

Final ASH13 SnapShot: AbbVie’s ABT-199

Update on ABT-199. 12-3-2013, by @PDRennert 

I reviewed the status of ABT-199 back in August, following ASCO (see link). At the time I felt the drug was being overlooked in the hype around ibrutinib and idelalisib. This was based on impressive response rates and the sense that AbbVie had gotten a handle on how to dose safely. After all, tumor lysis syndrome (TLS) is not uncommon in the treatment of lymphomas, and can be dealt with by dose modification or intervention.

At ASH we get a further look at this drug. Abstract #872, to be presented by J. Seymour, introduces a modified dosing regimen. Patients (rrCLL/SLL, n = 56) were given single doses of ABT-199 at day -3 or day -7, then started on daily dosing after that. This is a Phase 1 monotherapy trial designed to determine MTD. The efficacy readouts were pretty dramatic. ORR = 84% with CR = 21% and PR = 63%. Within the CR group (n = 12), 8 patients had no or very low minimal residual disease. There were 12 discontinuations due to progressive disease (21%). The response rate was not related to del(17p) status but the PR rate was lower in fludarabine-refractory patients (these patients are all at high risk).

Notably, among the usual AEs (diarrhea, neutropenia, URIs, etc) there was an 11% grade 3/4 TLS rate. This is 6 patients. Problematically, TLS was not clearly dose associated: 2 @ 50mg, 1 @ 100mg, 2 @ 200mg and 1 @ 1200mg, this last one resulting in sudden death. So dose optimization remains in progress.

The observation that response was not related to del(17q) status or other aberrations in the TP53 locus in rrCLL patients will be discussed in more detail by M.A. Anderson (Abstract #1304).

M. Davids (Abstract #1789) will present a similar study in a variety of rrNHL patients, including MZL, MCL, DLBCL, FL and WG. Of the 32 patients enrolled and followed for a median time of 6 months, 18 discontinued due to progressive disease (that’s 56%). AEs were typical (nausea, diarrhea, cytopenias, URIs). There were 2 mild episodes of TLS. For FL and DLBCL, doses of 600mg or higher were required for efficacy. The responses were good given this difficult mix of patients. Note that the text and table in this abstract don’t entirely line up, so best to hear the current results at the meeting. The implication here however is that ABT-199 is safer in these patient populations than in rrCLL, a theme we also heard at ASCO.

Aside from the clinical data there is an awful lot of preclinical modeling using cell lines or patient derived cells in vitro or in vivo (mouse). The point of all this nice work is to show the potential of combination therapy using ABT-199 along with other drugs. A few examples:

-  2-DG + ABT-199 kills all Myeloma subtypes (#1921)

-  ibrutinib + ABT-199 is effective against MCL cells and CLL cells (#645 and # 3080)

-  imatinib + ABT-199 kills chronic phase CML cells

-  BTK inhibitor R406 + ABT-199 kills DLBCL cells

   etc, etc

The CML observation points to another trend, which is efficacy of ABT-199 in settings beyond NHL, including ALL (#3919), AML (#885) and MM (#4453). There are others…

On balance this remains an exciting and potentially important drug. The issue of TLS in certain subtypes of NHL remains to be solved, while in other, difficult NHLs there appears to be clear and compelling efficacy with less toxicity.