Category Archives: JAK inhibitors

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.

Inflammation, autoimmunity & oncology drug development questions for 2014: RA

I think we’d all agree that 2013 was an exciting year for biotech and pharma drug development. New drug approvals, great late stage clinical trial results and exciting scientific data gave us all a wealth of topics to think about and discuss. There will be much more of this in 2014 and we can expect the excitement to continue. In the middle of all this however sits a big pile of unresolved questions and a plethora of diseases for which new therapies remain few of lacking. I want to pull a few things off that pile and have a look. What follows is a short list of drug development questions in the fields of inflammation, autoimmunity and oncology.

1) Will the use of biologics for Rheumatoid Arthritis (RA) begin to taper?

The blockbuster TNF antagonists Remicade, Enbrel and Humira continue to dominate the market for disease-modifying RA therapies (DMARDs). These drugs, other anti-TNF drugs, Stelara (anti IL-6 antibody), Orencia (CTLA4 fusion protein) and Rituxan (CD20 antibody) have transformed RA patient care to the point that the Rheumatologist’s goal has become disease remission.

Two challenges to the dominance of biologics were brought forward in 2013. One was the hypothesis that “triple therapy” – the use of a combination of the old and cheap chemical drugs methotrexate, sulfasalazine and hydroxchloroquine was just as effective as a TNF antagonist with or without methotrexate. This debate played out at the American College of Rheumatology conference in November. The consensus view that emerged was that triple therapy was effective for patients with mild RA who could tolerate the regimen. The problem is that triple therapy is very unpleasant and compliance can be very poor, especially in younger patients. The debate, while energetic, does not seem to have had an impact on the biologics market in RA.

The second challenge was brought on by the approval of Pfizer’s Jak2 inhibitor, a once-daily oral drug. Orals are considered the holy grail of RA drug development, allowing patients to move off of therapies that require either IV injections (in a health care setting) or subcutaneous injections (in a health care setting or self-administered). All approved biologics for RA are injectable drugs.

I reviewed Pfizer’s Jak2 inhibitor Xeljanz (tofacitinib) a while ago.

As discussed in that earlier post, Xeljanz showed impressive efficacy in RA clinical trials, and as approved by the FDA for use in methotrexate-refractory patients. This second-line label meant that patients did not have to try a biologic first, they could go directly to this nice, convenient once-a-day oral. So what happened?

Not much. Physicians balked at some of the side effects, and payers balked at the cost. The result was that this presumed blockbuster oral drug has posted very poor sales to date. It may be that Xejanz gains traction over time, we’ll have to see, but already we can take away several interesting lessons. One is that physicians have gotten comfortable with biologics, and being an oral drug does not automatically confer advantage. The second, which is really an old lesson, is that drug efficacy is paramount, and new drugs need to offer better efficacy. This is especially true if they are bringing some side-effect baggage along with them.

Is anything else in development that can challenge the established biologics in the near term? I think the short answer is no. Apremilast, Celgene’s PDE4 inhibitor, has trialed well in psoriatic arthritis and psoriasis, but did poorly in RA trials, so poorly that scheduled trials were terminated or withdrawn. Other Jak inhibitors and Syk, BTK and other inhibitors are currently in RA trials, but these are years away from approval. Some, like the Syk inhibitors fostamatinib from Rigel/Astra Zeneca and PRT062607 from Portola/Biogen Idec, have already failed.

Perhaps the next hurdle for the RA biologics will be the launch of biosimilar products, essentially generic versions of the antibody or protein. Thats a topic for another time.

In section 2 we will turn to an autoimmune disease that remains very poorly treated.

ASH 2013 preview: Myeloproliferative Neoplasms, New Targets

November 25, 2013. by P.D. Rennert (I keep forgetting to sign these entries)
Part 6b. Myelofibrosis and related Myeloproliferative Neoplasms: Phase 1 and preclinical updates from ASH 2013.

The American Society of Hematology Meeting will take place in New Orleans, December 7 – 10, 2013. The abstracts are available at http://www.hematology.org/Meetings/Annual-Meeting/Abstracts/5810.aspx
 
Back to it. In part 6a we looked at the phase 2/3 studies, and these are certainly focused on Jak inhibition, for reasons we discussed in part. Its worth noting that Jaks are a class of signaling proteins that hybridize shamelessly and because of this blocking any given Jak (Jak1, Jak2, Jak3, Tyk2) will necessarily block the activity of others in the context of signaling that requires hybridization. Conversely it has been demonstrated that blocking any given Jak may not be effective in settings where other family members can substitute. As always, it is complicated.
 
It has been mentioned that Jak inhibitors are not considered disease modifying or curative. They offer symptomatic relief, which relieve the pathological degradation of the bone marrow, and can do so for extended periods, as has been demonstrated with ruxolitinib. In this sense the treatment paradigm is not so different from some other targeted cancer therapies, where the name of the game is to keep the wolf from the door, at least for a time.
 
Regardless of the limited potential, Jak inhibitor development continues at a brisk pace, as demonstrated in the previous section. In earlier development we find yet more Jak inhibitors. Gilead will present data from the phase 1/2 trial (with extension) of the Jak1/2-selective inhibitor, momelotinib (Abstract #108). Confusingly, this trial used some new (to me) endpoints. One was a reduction in “palpable splenomegaly” which suggests the spleen was not imaged (?). Second (and useful I think) was “transfusion independence”. I like this because it clinically measures the impact of treatment on the most pathologically relevant endpoint, loss of RBCs and platelets in circulation. What is even more interesting about this trial is the extension data, showing a “median spleen response” of 324 days, with pretty huge variance. As noted with ruxolitinib, the variance cannot be traced to the presence or absence of Jak2 V617F mutation - I suspect Gilead will work to sort this out pretty quickly, so that bears watching unless of course the variance is due to the manner of measurement!
 
Early trial data will be reported for BMS911543, another Jak2-selective inhibitor (Abstract #664). Note that Jak3 and Tyk2 are hit with IC50s less than 100nM, so selectivity will depend on actual exposure, which is data not available yet. Anyway, the drug is given BID and the goal of the trial is to establish an MTD (not reached). Early efficacy data included analysis of responses of patients who had received a prior Jak inhibitor. Symptoms were well controlled and the spleen volume response (> 35% reduction in splenomegaly) was dose responsive – up to 70% of patients responded at the highest doses (note: small sample size). AEs were were the usual diarrhea, nausea and cytopenias. The investigators will update with data from 84 patients at the meeting.
 
Eli Lilly will present data from the LY2784544 phase 1 dose escalation trial (Abstract #665). Of note, this drug is described as being “selective” for the V617F mutant of Jak2. They are enrolling 38 patients (most MF, some PV) at 30 -300 mg per day, although at 200 mg and above they hit liver tox (grade 3 serum creatinine elevation) and the MTD is established at 120 mg/day. Other AEs are typical of the class and not severe. We are introduced to yet another way of measuring splenomegaly, this time as “spleen length”. There was a >50% improvement in 56% of the evaluable patients, furthermore, >50% of patients reported improved symptoms by TSS. An update is promised for the meeting.
 
Novel inhibitors are finally moving through preclincal and early clinical evaluation. Geron has a novel telomorase inhibitor, imetelstat, a lipid-conjugated oligonucleotide inhibitor of human telomerase (Abstract #662). Early data are impressive. AEs were modest, and responses (44%) included a fair number that appeared to be CRs or PRs. Here I quote: 
 
“The four (22%) CR patients experienced reversal of BM fibrosis and recovery of normal megakaryocyte morphology. Two CR patients were transfusion-dependent at baseline and became transfusion-independent … Among 13 patients with leukocytosis, 10 (77%) normalized their count or had >50% reduction. Eleven (61%) patients had complete or partial resolution of leukoerythroblastosis.”
 
Thats pretty impressive. The downside is that this was a small single center open label trial, so really, we just have to wait and see.
 
For an example of why such results can be so misleading, let look at a Phase 3 trial failure (Abstract #394). Here we have Celgene’s pomalidomide (approved under the name Pomalyst for the treatment of Multiple Myeloma). Phase 2 trials suggested that pomalidomide imporved severe anemia in MPN patients, including MF, PV and ET patients. The phase 3 trial enrolled 252 patients with MPN-associated MF who were dependent on RBC transfusions. There was no significant improvement in time to transfusion in drug-treated v placebo-treated cohorts.
 
So these early trials can be very misleading, but lets look even earlier, at some preclinical studies.
 
Novartis has some nice data showing elevation of Hedgehog signaling pathway targets in MF granulocytes (Abstract #666). Using in vitro and in vivo (mouse) models they demonstrate that Jak inhibition and Hedgehog inhibition have additive activity. The Jak inhibitor was INC424 and the Hedgehog inhibition was provided by Smoothened antagonism (sonidegib). Another novel approach is to target megakaryocytes, that contribute to MF pathogenesis. Using in vitro and in vivo models an academic collaboration (Abstract #109) shows that Aurora A kinase inhibition induces megakaryocyte arrest and this results in decreased bone marrow fibrosis, decreased infiltration of megakaryocytes and granulocytes into the liver and spleen, and decreased plasma TGFbeta, a potent pro-fibrotic growth factor.
Genetic analyses have demonstrated that certain signatures indicate risk for increased risk of leukemic conversion and decreased OS. These include ASXL1, EZH2, IDH1/2 and SRSF2 gene mutations (Abstract #104). EZH2 mutation accelerates the onset of primary MF (Abstract #110). However, patients carrying these mutations are not differentially impacted by ruxolitinib therapy, instead they have similar responses to patients without such mutations (Abstract #105). Novel pathways associated with MF include the arachidonate 5-lipoxygenase pathway (Abstract #111). An exciting new development is the identification of calreticulin mutations in patients that do not have Jak2 mutations, that is, the two appear to be mutually exclusive (Abtract #LBA1). This will spur investigation in novel drivers of MPN pathogenesis.
Obviously there is much more going on then can be covered here. The identification of the Jak2 mutation in MPN opened up a new era of drug development for these rare but nasty and lethal neoplasms. New findings will push us even further, and we can reasonably expect to see important advances over the next few years.
 
 

ASH13 SnapShots, part 6, Myelofibrosis: How Many Jak Inhibitors Are There?

November 25, 2013. by P.D. Rennert (I keep forgetting to sign these entries)

Part 6a. Myelofibrosis: Therapeutic agents in Phase 2/3.

The American Society of Hematology Meeting will take place in New Orleans, December 7 – 10, 2013. The abstracts are available at http://www.hematology.org/Meetings/Annual-Meeting/Abstracts/5810.aspx

I’m splitting this into 2 parts because, well, lets just say there is always a lot to learn. Myelofibrosis is a proliferative cancer of myeloid lineage cells, characterized by bone marrow infiltration and fibrosis, splenomegaly and heptomegaly caused by extramedullary hematopoiesis, and overall disruption of hematopoiesis leading to cytopenic conditions such as anemia and thrombocytopenia. Patients experience diverse symptoms, which has led to the development of patient symptom scoring systems. They are at risk for transformation to acute myeloid leukemia, and in general have greatly reduced overall survival due to chronic anemia leading to bone marrow failure.

Myelofibrosis (MF) is one of a class of myeloproliferative neoplasms (MPN) that also includes Polycythemia Vera (PV) and Essential Thrombocytopenia (ET). In 2005 it was found that nearly all PV cases and about half of MF and ET cases had a mutation in Jak2 (V617F). This marked the beginning of novel drug development for MPN that culminated with the 2011 approval of ruxolitinib (Jakafi) for the treatment of intermediate risk (intermediate-2) or high risk MF. Ruxolitinib is a Jak1/Jak2-selective inhibitor.

The clinical landscape for MF remains dominated by Jak inhibitors, and to go through them is an exercise in duration. Lets spare you all that, and try to summarize quickly, hitting high and low points when they appear. At the outset its fair to make a few generalizations. First, Jak inhibitors are not curative and do not induce PRs or CRs in the way we have discussed in earlier sections. Second, Jak inhibitors themselves can cause cytopenias, and they are therefore dose or duration limited. So, this becomes a balancing act between efficacy (by inhibition of myeloid-lineage cell proliferation) and toxicity (due to inhibition of hematopoiesis). 

Lets sort these by clinical stage.

Sanofi is presenting results from a phase 3 trial of fedratinib, a Jak2-selective inhibitor (Abstract #393). In this trial of patients with high risk or primary (i.e. active) MF the primary endpoints are splenomegaly and patient reported symptoms. Patients have to present with platelet counts above 50 x 10^9/L. 67% of the patients were positive for the V617F Jak2 mutation. 40% of evaluable patients reached the spleen response rate of > 35% reduction in spleen volume as measured by MRI or CT. About the same percent recorded improvement in platelet counts and about 30% of patients reported improved symptoms. This is very much like the ruxolitinib results, as are the AEs reported, which include diarrhea, anemia, higher risk for infection, among others.

UPDATE: via FierceBiotech “A few days ago the pharma giant had to shutter a program for fedratinib after the FDA ordered a clinical halt when their myelofibrosis patients developed Wernicke’s encephalopathy–a neurological condition spurred by biochemical brain lesions.”

Well, thats the end of that drug (another abstract below, just to be thorough). This tox issue is clearly not a class effect, that is, not a Jak inhibitor issue. Instead this drug either hits another signaling or other protein target (that might be interesting). Alternatively, and perhaps more likely, this is compound specific toxicity. Either way, the fact that this tox issue was missed until now (phase 3) is remarkable.

Sanofi also has results (Abstract #661) from a phase 2 trial of fedratinib in MPN patients who were previously on ruxolitinib (so these are ruxolitinib resistant or intolerant). These patients presented with splenomegaly, as evidence of disease activity, and had to have platelet counts above 50 x 10^9/L. The presentation is of results obtained at the 12 week interim cutoff point. Somewhat remarkably (to me anyway) the spleen response rate (defined above) was about 40%. The patient reported outcome was modest, but measurable. This suggests that moving from one Jak inhibitor to another is not as silly as it might sound (we’ve seen this before: anti-TNFs in RA; IFN betas in MS). The downside was the toxicity: 26% of patients discontinued due to AEs that included some grade 3/4 (severe) diarrhea, and a very high rate of anemia and thrombocytopenia. It will be important to track patient outcomes and AEs going forward in this trial.

Incyte will report on a Jak1-selective inhibitor INCB039110 that is in an open-label MF Phase 2 trial (Abstract #663). The primary endpoint in this trial is patient reported symptom score (TSS). Inclusion/exclusion criteria were similar to what is described above. While there was a dose dependent improvement in TSS, there was only a modest improvement in the more objective endpoint of change in spleen volume. Importantly however, Hb level (a measure of RBC count) and platelet counts were preserved. This suggests that Jak1 inhibition might be useful, assuming that there is reasonable efficacy.

Just to remind us how confusing this all can be, Cell Therapeutics will present results obtained in a Phase 2 trial of its Jak2.Flt3 dual inhibitor, pacritinib (Abstract # 395). This trial enrolled patients with primary or secondary MF and included patients whose platelet counts were below 100,000/microliter. This low number is prognostic for transformation to a leukemic state and further, patients with such low counts were specifically excluded from the ruxolitinib registration trials (COMFORT III). 82% of patients had the Jak2 V617F mutation. So, Cell Therapeutics is trying to differentiate pacritinib here, and they are successful. Approximately 40% of patients achieved > 35% reduction in spleen volume. Most patients maintained stable platelet numbers if Hb levels. Notable also were the modest AEs reported. This is an interesting therapeutic to watch.

Next we’ll look at some earlier therapeutics, including novel (i.e. non-Jak targeting) therapies, coming up in part 6b.

Syk inhibitors continue to struggle in the clinic

Syk inhibitors have had a rough ride, with both Rigel and Portola running into significant issues in clinical development.

Rigel and partner Astra Zeneca released data from a Phase 2 Rheumatoid Arthritis study, summarized here:

“In the study known as OSKIRA-1, two doses of fostamatinib significantly improved the signs and symptoms of rheumatoid arthritis compared to a placebo following 24 weeks of treatment. However, fostamatinib failed to show improvements over placebo in bone erosion and joint-space narrowing as measured by X-ray.” from http://www.thestreet.com/story/11888193/1/astra-rigel-arthritis-pill-posts-mixed-trial-results.html).

Sadly thats about all you need to know about fostamatinib, especially given that earlier data have been unimpressive as we discussed in December. There is no clear role for this drug in RA given the label granted to Pfizer for their JAK inhibitor tofacitinib, approved for use as second line therapy for RA. Tofacitinib also has shown clear evidence of protection from joint damage, something fostamatinib has failed to do.

Fostamatinib is apparently moving forward in multiple oncology indications, and therein may lie its future, if it has one.

Portola’s Syk inhibitor, licensed by Biogen Idec, is in development limbo, and the clinical trial in RA was withdrawn. Whether this is due to toxicity issues, efficacy concerns, or commercial strategy is not known, as Biogen has not provided an update on this drug.

In the meantime companies continue to focus on kinases that signal downstream of Syk, notably Btk and PI3K. While PI3K inhibition may carry too much toxicity for use outside of oncology, Btk inhibitors appear to be safe enough to develop in autoimmunity and inflammation. We will continue to watch the development of small molecule inhibitors in this space, and anticipate success for novel Btk inhibitors.