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« on: January 08, 2011, 12:33:09 PM »

Avoiding spleen removal for Cooley's anemia sufferers
Published: Wednesday, May 28, 2008 - 20:28 in Health & Medicine
Researchers from Weill Cornell Medical College may have discovered the precise role of a gene in one of the world's most common blood disorders, beta-thalassemia, commonly known as Cooley's anemia. Along with sickle-cell anemia, Cooley's anemia is the most commonly inherited disease in the world, affecting many people of Mediterranean descent, and 20 out of every 100,000 African-Americans. The World Health Organization estimates that between 50,000-100,000 children are born with the disease each year. The research is published in the latest online issue of the journal Blood, the official publication of the American Society of Hematology (ASH).

In Cooley's anemia, hemoglobin -- the oxygen-carrying molecule on red blood cells -- is mutated and non-functioning, resulting in a low red-blood-cell count. Common symptoms of the disease include fatigue, shortness of breath and an enlarged spleen, called splenomegaly, caused by a buildup of malformed red blood cells within the body. The spleen works to filter out these unhealthy cells in order to protect the body from harm, such as in a stroke, but eventually the spleen becomes over-stuffed and is commonly surgically removed (splenectomy) in order to prevent a potentially fatal burst. Unfortunately, after the spleen is removed, patients are at a much greater risk for stroke and infections.

Dr. Stefano Rivella, the study's senior author and assistant professor of genetic medicine in pediatrics at Weill Cornell Medical College, in New York City, believes that he and his collaborators may have found a way around splenectomy. After giving mice with Cooley's a compound called JAK2 inhibitor, the researchers found that the mice's spleens shrunk to normal sizes, and they began to produce normal red blood cells. The chemical (a similar compound is already in a Phase I clinical trial for myelodysplastic syndromes -- another blood disorder) blocks the activity of the JAK2 gene that is highly expressed in Cooley's anemia, and is believed to play a crucial role in the malformation of red blood cells.


does anyone know about the clinical trial?
it may be beneficial for us.
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« Reply #1 on: January 09, 2011, 10:58:12 AM »

Too much Jak2 causes polycythemia / erythrocytosis.

http://www.nhlbi.nih.gov/health/dci/Diseases/poly/poly_causes.html


What Causes Polycythemia Vera?
Polycythemia vera (PV) also is known as primary polycythemia. A
mutation, or change, in the body's JAK2 gene is the main cause of PV.
The JAK2 gene makes an important protein that helps the body produce
blood cells.


What causes the change in the JAK2 gene isn't known. PV generally
isn't passed from parent to child. However, in some families, the JAK2
gene may have a tendency to mutate. Other, unknown genetic factors
also may play a role in causing PV.


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« Reply #2 on: January 09, 2011, 06:25:04 PM »

I do not believe that this has been scheduled for trial in humans yet. The studies were done using mice. Dr Rivella gave a talk on the subject of Jak2 inhibitors the the NYC conference in 2009. Sharmin and I were at the lecture. This is the abstract from that lecture. This is from the New York Academy of Science site.

Quote
Iron Regulation And Ineffective Erythropoiesis, Jak 2

Luca Melchiori, PhD1, Sara Gardenghi, PhD1, Ella Guy1, MD.2, Domenica Cappellini, MD3, MD1, Robert W. Grady, PhD.1, Stefano Rivella, PhD1 , 1Department of Pediatric Hematology-Oncology, Weill Medical College of Cornell University, New York, NY; 2E. Wolfson Medical Centre, Institute of Hematology, Holon, Israel, 3Centro Anemie Congenite, Fondazione Policlinico, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), University of Milan, Milan, Italy

In thalassemia, ineffective erythropoiesis is characterized by apoptosis of the maturing nucleated erythroid cells. Our studies also suggest that limited erythroid cell differentiation plays a role in the development of ineffective erythropoiesis. Some of the major consequences of ineffective erythropoiesis are extra−medullary hematopoiesis (EMH), splenomegaly and systemic iron overload mediated by transfusion therapy and down−regulation of hepcidin. Recall that under conditions of chronic anemia, low levels of hepcidin lead to iron overload. We hypothesized that the protein kinase Jak2, which controls erythroid cell proliferation, plays a major role in exacerbating ineffective erythropoiesis. Therefore, use of Jak2 inhibitors may limit the overproduction of immature erythroid cells in thalassemia, with the potential of reversing extramedullary hematopoiesis and preventing splenectomy. For this reason, we administered a Jak2 inhibitor to mice affected by beta−thalassemia intermedia for 10 days, showing that this treatment was associated with a marked decrease in ineffective erythropoiesis, splenomegaly, no or with little or no reduction of red cell production and no side effects.

There is a clear correlation between the mass of erythroid precursors and suppression of hepcidin. Therefore, administration of a Jak2 inhibitor might also be associated with increased hepcidin synthesis and decreased iron absorption. In order to test this hypothesis we repeated the above-mentioned study in order to evaluate the level of hepcidin expression as well as that of other iron related genes. This analysis clearly indicated that the size of the spleen inversely correlated with hepcidin synthesis. In addition, blood transfusion is a pre-requisite for the management of both thalassemia−major patients and those with thalassemia−intermedia who develop splenomegaly. Therefore, administration of a Jak2 inhibitor, together with blood transfusions, might be a sensible way to further suppress ineffective erythropoiesis and limit splenomegaly/EMH. We conducted an analysis of erythropoiesis and iron metabolism in animals affected by beta−thalassemia major, which require blood transfusion for survival and compared them to transfused animals treated with placebo. Compared to latter controls, the animals treated with the Jak2 inhibitor showed a dramatic decrease in splenomegaly, amelioration of the spleen architecture and complete elimination of EMH in the liver. In addition, due to the reduction of the size of the spleen, the animals treated with the Jak2 inhibitor showed higher levels of hemoglobin at the end of the treatment, again, the spleen size inversely correlating with hepcidin synthesis. These experiments suggest that this class of compounds, if safe, might be an important tool to prevent splenectomy, reverse EMH, limit iron absorption and improve the effectiveness of transfusion therapy in patients with thalassemia.

At this point, it is one more potential approach to treating thalassemia. I am posting the abstracts from the entire session at
http://www.thalassemiapatientsandfriends.com/index.php?topic=3823.msg38437#msg38437
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Andy

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« Reply #3 on: January 10, 2011, 01:13:47 PM »

Andy,
i didn't find any clinical trials for beta thalassemia using JAK2 inhibitor but it is being used for other diseases.
is there a possibility that once it comes in the market, it could be used by thals?
some of the trials were in phase 2
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« Reply #4 on: January 10, 2011, 01:20:35 PM »

Interesting question. I would say that once it's approved for other conditions, there may be doctors willing to try it for thal, even if it hasn't been trialed specifically for thal, just as there were doctors prescribing the Exjade/desferal combination as soon as Exjade was approved.
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« Reply #5 on: January 10, 2011, 10:52:25 PM »

brilliant! i'll post the status of the trials in a bit.
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« Reply #6 on: January 11, 2011, 11:58:42 AM »

Could you please look at this:
http://www.emdchemicals.com/life-science-research/jak2-inhibitor-iii-sd-1029/EMD_BIO-573098/p_WkSb.s1O7mcAAAErMhkqPdBL
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« Reply #7 on: January 11, 2011, 12:06:40 PM »

I believe that the products listed here are for sale for research purposes and are not intended for prescription purposes. I would not recommend self experimentation with this. Until thorough trials have been completed to rule out any unforeseen problems with the drug, it is never wise to use it.
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« Reply #8 on: January 11, 2011, 12:52:28 PM »

Found 10 clinical trials with JAK2 inhibitors
Rank Status Study
1 Active, not recruiting  This is a Study to Determine the Effect and Safety of an Oral Janus Kinase 2 (JAK2)-Inhibitor in Patients With Multiple Myeloma Conditions:  Relapsed Multiple Myeloma;   Refractory Multiple Myeloma;   Multiple Myeloma
Intervention:  Drug: INCB018424 Phase II

 
2 Recruiting  Study of INCB018424 for Acute Leukemia Condition:  Leukemia
Intervention:  Drug: INCB018424 Phase I Phase II
 
3 Recruiting  Open Label INCB018424 in Patients With Myelofibrosis and Post Polycythemia Vera/Essential Thrombocythemia Myelofibrosis Conditions:  Myelofibrosis;   Polycythemia Vera;   Thrombocytosis
Intervention:   Phase I Phase II
 
4 Recruiting  Study to Assess the Safety of AZD1480 in Patients With Myeloproliferative Diseases Conditions:  Primary Myelofibrosis (PMF);   Post-Polycythaemia Vera;   Essential Thrombocythaemia Myelofibrosis
Intervention:  Drug: AZD1480 Phase I Phase II
 
5 Recruiting  A Study in Patients With Rheumatoid Arthritis on Background Methotrexate Therapy Condition:  Arthritis, Rheumatoid
Interventions:  Drug: LY3009104;   Drug: Placebo Phase II

 
6 Active, not recruiting  A Phase 1/2 Study of Oral SB1518 in Subjects With Chronic Idiopathic Myelofibrosis Conditions:  Myelofibrosis;   Myeloproliferative Disorders;   Polycythemia Vera;   Essential Thrombocythemia
Intervention:  Drug: SB1518 Phase I Phase II

 
7 Active, not recruiting  A Phase 1/2 Study of SB1518 for the Treatment of Advanced Myeloid Malignancies Conditions:  Acute Myelogenous Leukemia;   Chronic Myelogenous Leukemia;   Chronic Myelomonocytic Leukemia;   Myelodysplastic Syndromes;   Myelofibrosis
Intervention:  Drug: SB1518 Phase I Phase II

 

 
9 Recruiting  A Study of AZD1480 in Asian Patients With Advanced Solid Malignancies and Asian Patients With Advanced Hepatocellular Carcinoma Conditions:  Advanced Solid Malignancies;   Child-Pugh A to B7 Advanced Hepatocellular Carcinoma;   Solid Cancer Refractory to Standard Therapies;   Liver Cancer Refractory to Standard Therapies With Mild and Moderate Liver Function
Intervention:  Drug: AZD1480 Phase I

 
10 Recruiting  A Single and Multiple-Dose Study of SB1578 Condition:  Healthy Volunteer
Interventions:  Drug: SB1578;   Drug: Placebo Phase I

 
 


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« Reply #9 on: April 18, 2011, 02:54:08 PM »

YM BioSciences Reports Positive Updated Anemia Response Data for its JAK1/JAK2 Inhibitor CYT387 Disclosed at First Annual Florence Meeting on Myeloproliferative Neoplasms in Florence, Italy
PR Newswire

MISSISSAUGA, ON, April 18 /PRNewswire/ - YM BioSciences Inc. (NYSE Amex: YMI, TSX: YM), today announced that updated interim anemia response data were reported for the first 60 patients enrolled in the Phase I/II trial of its JAK1/JAK2 inhibitor, CYT387, for the treatment of myelofibrosis. The results were disclosed by Dr. Ayalew Tefferi (Mayo Clinic, Rochester, Minnesota), Chair of the Study, during the First Annual Florence Meeting on Myeloproliferative Neoplasms held in Florence, Italy on Saturday, April 16th, 2011.

"These results continue to highlight the potential for CYT387 to induce durable anemia responses, as demonstrated using these more rigorous measurement standards," said Dr. Nick Glover, President and CEO of YM BioSciences. "We look forward to reporting updated interim data on CYT387's safety and efficacy profile at the ASCO conference in June."

Dr. Tefferi reported that the overall anemia response rate was 58% in 33 transfusion-dependent patients. In this assessment, anemia response required a transfusion-free period of ≥12 weeks while on protocol drug therapy, with a minimum hemoglobin level of 8 g/dL.  The median duration of transfusion independence was reported to be 6 months (range 4-15 months).  Only 2 (11%) of the 19 patients who achieved transfusion-independency were reported to require single episodes of PRBC transfusions.

The results were based on data observed for the first 60 patients enrolled in the dose escalation (n=21) and dose confirmation (n=39) portions of the 140 patient Phase I/II trial, for which recruitment has now been exceeded. These 60 high/intermediate-risk myelofibrosis patients have received CTY387 orally once daily in 28-day cycles, and have completed a minimum of 3 cycles of treatment.

About CYT387:
CYT387 is an inhibitor of the kinase enzymes JAK1 and JAK2, which have been implicated in a family of hematological conditions known as myeloproliferative neoplasms, including myelofibrosis, and as well in numerous other disorders including indications in hematology, oncology and inflammatory diseases. Myelofibrosis is a chronic debilitating disease in which a patient's bone marrow is replaced by scar tissue and for which treatment options are limited or unsatisfactory. The U.S. Food and Drug Administration (FDA) has granted Orphan Drug Designation to CYT387 for the treatment of myelofibrosis.

YM BioSciences retains full global commercialization rights to CYT387.

For more information on the CYT387 Phase I/II trial, go to:
http://clinicaltrials.gov/ct2/show/NCT00935987?term=cyt387&rank=1

About YM BioSciences
YM BioSciences Inc. is a drug development company advancing three clinical-stage products: CYT387, a small molecule, dual inhibitor of the JAK1/JAK2 kinases; nimotuzumab, an EGFR-targeting monoclonal antibody; and CYT997, a potent vascular disrupting agent (VDA).

CYT387 is an orally administered inhibitor of both the JAK1 and JAK2 kinases, which have been implicated in a number of immune cell disorders including myeloproliferative neoplasms and inflammatory diseases as well as certain cancers. CYT387 is currently in a Phase I/II trial in myelofibrosis. Nimotuzumab is a humanized monoclonal antibody targeting EGFR with an enhanced side effect profile. Nimotuzumab is being evaluated in various Phase II and III trials worldwide by YM's licensees. CYT997 is an orally-available small molecule therapeutic with dual mechanisms of vascular disruption and cytotoxicity, and is currently in a Phase II trial for glioblastoma multiforme. In addition to YM's three clinical stage products, the Company has a library of more than 4,000 novel compounds identified through internal research conducted at YM BioSciences Australia which are currently being evaluated.

This press release may contain forward-looking statements, which reflect the Company's current expectation regarding future events. These forward-looking statements involve risks and uncertainties that may cause actual results, events or developments to be materially different from any future results, events or developments expressed or implied by such forward-looking statements. Such factors include, but are not limited to, changing market conditions, the successful and timely completion of clinical studies, the establishment of corporate alliances, the impact of competitive products and pricing, new product development, uncertainties related to the regulatory approval process or the ability to obtain drug product in sufficient quantity or at standards acceptable to health regulatory authorities to complete clinical trials or to meet commercial demand; and other risks detailed from time to time in the Company's ongoing quarterly and annual reporting. Certain of the assumptions made in preparing forward-looking statements include but are not limited to the following: that nimotuzumab will continue to demonstrate a competitive safety profile in ongoing and future clinical trials; that our JAK1/JAK2 inhibitor CYT387 and our VDA small molecule CYT997 will generate positive efficacy and safety data in future clinical trials; that YM and its various partners will complete their respective clinical trials within the timelines communicated in this release. Except as required by applicable securities laws, we undertake no obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.

SOURCE YM BioSciences Inc.

 
Copyright 2010 PR Newswire. All Rights Reserved
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« Reply #10 on: April 18, 2011, 03:41:34 PM »

These results look really good for preliminary trials likely using low doses.  The potential with higher doses and more knowledge can be great.  Let's keep our fingers crossed. 

Thank you for sharing L & P

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« Reply #11 on: April 25, 2011, 08:59:51 AM »

Incyte’s Pipeline in 2011


 Incyte could end the year with its first drug on the market with INCB18424. This drug is the co’s lead compound in clinical trials and, is a JAK-2 inhibitor which is currently in Phase III for myelofibrosis. Initial results were given in December 2010 and were positive, which suggests that if Incyte announce good final results by Q2 2011, than INCB18424 could get FDA approval by year end. In fact, this looks set to be the first approved JAK inhibitor for any indication. Incyte also has this drug in Phase II trials for Polycythemia Vera and Essential Thrombocythemia.


INCB18424 a JAK-2 Inhibitor in Phase III Trials for Myelofibrosis


Incyte is partnered with Novartis for this drug. However, there are another two JAK inhibitors that, according to the principal investigator for both, Mayo Clinic, are producing significant responses in myelofibrosis. The first drug is YM Bioscience’s CTY387. According to Ayalew Tefferi of Mayo Clinic…


‘CYT387 not only works to reduce spleen size and to help with other symptoms, but it is the first in its class to show a significant response rate in anemia in myelofibrosis patients’
…and this anemia response affect, would appear to give YM Bioscience an edge. However, I would caution against getting too worried for Incyte, just yet. This was a Phase I/II trial with only 36 patients and CYT387 is years-and clinical trials-behind INCB18424.  YM Bioscience is looking for a partnering deal and, I suspect they will get it. CYT387 reduced spleen size by 50% in 37% of patients who achieved spleen reduction (97% of patients) in this trial.


The other potential competitor is TargeGen’s TG101348 whose Phase I/II results were so impressive that Sanofi-Aventis bought the company. More studies are underway.  Although the results were impressive, they too, are years behind Incyte’s drug. According to Mayo, TG101348 reduced spleen size by 50% in 72% of the responders (95%) in the trial.


As for INCB18424, Incyte released data from the Phase III trial involving 309 patients




The primary endpoint was the response rate defined as the percentage of patients achieving a 35% or greater reduction in spleen volume at 24 weeks as measured by magnetic resonance imaging, or computerized tomography, comparing the rates in patients receiving INCB18424 or placebo. The response rate was 42% in patients randomized to INCB18424 versus less than 1% of patients randomized to placebo
The drug is also in a European 219 patient Phase III, trial, with results due by mid 2011.  According to the JP Morgan Presentation, Incyte feel that there are 16-18,500 myelofibrosis sufferers in the US and the potential pricing could be around $50k. They believe there are 95,000 PV/ET sufferers.


Assuming, they grab 25% of the myelofibrosis market (not all sufferers will be eligible) and 10% of the PV/ET markets this could give around 14k*50k=700m in US revenue in 5-6 years. A hand waving guess sees Ex-US sales royalty bringing in 10% of that figure, so possibly around 770m.


In addition, this is the type of indication that will see favorable demographics in future years, as the amount of older people increases.
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« Reply #12 on: May 13, 2011, 10:01:30 AM »

Oral JAK2 Inhibitor
May 4, 2011
From Medical News Today,

Pfizer Announces Top-Line Results Of Final Two Pivotal Phase 3 Trials Of Tofacitinib (CP-690,550) In Patients With Active Rheumatoid Arthritis

Article Date: 03 May 2011 – 10:00 PDT

Pfizer Inc. announced today top-line results from the ORAL Standard (A3921064) and ORAL Step (A3921032) Phase 3 studies of tofacitinib (development code: CP-690,550), an investigational, novel, oral JAK inhibitor.

ORAL Standard is a completed twelve-month study in patients with moderate-to-severe active rheumatoid arthritis (RA) who had an inadequate response to methotrexate (MTX) and were randomized to receive tofacitinib 5 or 10 mg BID, adalimumab 40 mg subcutaneously every other week or placebo, each of which was added to stable background MTX.

The ORAL Standard study met all primary endpoints at the 5 and 10 mg BID doses of tofacitinib, showing statistically significant changes versus placebo in reducing signs and symptoms of RA, as measured by ACR20 response rates at six months; in improving physical function, as measured by mean change in HAQ DI at three months; and in reaching DAS28-4(ESR) <2.6 at six months.

ORAL Step is a completed six-month study in patients with moderate-to-severe active RA who had an inadequate response to a TNF inhibitor and were randomized to receive tofacitinib 5 or 10 mg BID or placebo, which were added to stable background MTX.

The ORAL Step study met all primary endpoints at the 5 and 10 mg BID doses, showing statistically significant changes versus placebo in reducing signs and symptoms of RA, as measured by ACR20 response rates; in improving physical function, as measured by mean change in HAQ DI; and in reaching DAS28-4(ESR) <2.6, all assessed at three months.

No new safety signals emerged in the ORAL Standard and ORAL Step studies. The efficacy and safety profile of tofacitinib in these studies remains consistent with that seen previously in the clinical program.

A detailed analysis of the ORAL Standard and ORAL Step efficacy and safety data, including secondary endpoints which are not reported here, will be submitted to a future scientific meeting.

About ORAL Standard (A3921064)

ORAL Standard is a twelve-month study that enrolled 717 patients with moderate-to-severe active RA who had an inadequate response to MTX to receive tofacitinib 5 or 10 mg BID or adalimumab 40 mg subcutaneously every other week or placebo, each of which was added to stable background MTX. Patients who had previously received adalimumab or had an inadequate response to a TNF inhibitor were excluded from participation. Patients were randomized such that at the month-three visit, nonresponding placebo-assigned patients were advanced in a blinded fashion to a predetermined treatment of tofacitinib, 5 or 10 mg BID, for the remainder of the study; at the end of six months, all placebo-assigned patients were advanced to their predetermined tofacitinib treatment assignment in a blinded fashion for the remainder of the study. Those patients assigned to 5 or 10 mg BID tofacitinib or adalimumab 40 mg every other week at the start of study remained on those dose regimens throughout the 12 months of the study.

About ORAL Step (A3921032)

ORAL Step is a six-month study that enrolled 399 patients with moderate-to-severe active RA who had an inadequate response to at least one TNF inhibitor to receive tofacitinib 5 or 10 mg BID or placebo added to stable background MTX. Those patients were randomized such that at the month-three visit, placebo-assigned patients were advanced in a blinded fashion to a predetermined treatment of tofacitinib, 5 or 10 mg BID, for the remainder of the study. Those patients assigned to 5 or 10 mg BID tofacitinib at the start of study remained on those dose regimens throughout the six months of the study.

About Rheumatoid Arthritis

Rheumatoid arthritis is a chronic inflammatory autoimmune disease that typically affects the hands and feet, although any joint lined by a synovial membrane may be affected. RA affects approximately 1.3 million people in the U.S. 1 and one percent of the adult population worldwide.2

About Tofacitinib

Tofacitinib is a novel, oral Janus kinase (JAK) inhibitor that is being investigated as a targeted immunomodulator and disease-modifying therapy for RA. More than 4,000 RA patients have been treated with tofacitinib in clinical trials to date. Unlike more recent therapies for RA, which are directed at extracellular targets such as pro-inflammatory cytokines, tofacitinib takes a novel approach, targeting the intracellular signaling pathways that operate as hubs in the inflammatory cytokine network.

Pfizer is studying tofacitinib for RA in the Phase 3 ORAL (Oral Rheumatoid Arthritis Phase 3 TriaLs) program, which consists of five pivotal trials and a sixth long-term treatment study at more than 350 locations in 35 countries worldwide. ORAL Standard and ORAL Step are the final two pivotal trials in the program.

Pfizer is also studying orally administered tofacitinib in psoriasis, inflammatory bowel disease (Crohn’s disease and ulcerative colitis) and renal transplant, and topical tofacitinib in both psoriasis and dry eye disease.

1 Arthritis Today. “What is Rheumatoid Arthritis.” Accessed 24 February 2011. Available at: http://www.arthritistoday.org/conditions/rheumatoid-arthritis/all-about-ra/what-is-ra.php.

2 Rubbert-Roth A, Finckh A. Treatment options in patients with rheumatoid arthritis failing initial TNF inhibitor therapy: a critical review. Arthritis Res Ther. 2009; 11(Suppl 1): S1.Published online 2009 April 6. doi: 10.1186/ar2662.

Source:
Pfizer Inc.

Another DMARD is likely to enter the market. The best part of this is the oral administration, negating the need to self-inject or infusions which seem to irk quite a few patients.

http://rheumatology.my/?p=541
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« Reply #13 on: May 24, 2011, 01:37:56 PM »

I am sure I was told about this during Conference 2011..
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« Reply #14 on: October 06, 2011, 11:18:26 AM »

Advances in treatment for myelofibrosis (MF) have come by leaps and bounds in the last few years since the discovery of the activating mutation JAK2V617F in the cells of patients with myeloproliferative disorders including MF, polycythemia vera, and essential thrombocytopenia. Incyte’s (INCY) JAK inhibitor, ruxolitinib (INCB018424), looks to be the first drug to reach approval for the disorder, but a slew of competitors are following suit.
MF is characterized by anemia, bone marrow fibrosis, enlarged spleens, fatigue, bone pain, and a constellation of debilitating symptoms. Current treatment is primarily palliative; the option with any curative potential is an allogenic stem cell transplant, however the procedure carries significant risk of morbidity.
Along come the JAK2 inhibitors: ruxolitinib, SB1518, TG101348, XL019, CYT387, AZD-1480, R723, LY2784544, among others based on the premise that aberrant JAK2 signaling is the causative factor in the majority of myeloproliferative disorders. Eventual research has shown this is not the case; other pathways unrelated to JAK were also involved. Even so, these compounds have shown significant efficacy to date.
Ruxolitinib and CYT387 appear to be the top contenders. Interestingly, both have similar profiles, inhibiting JAK1 and JAK2 (the JAK family consists of JAK1, JAK2, JAK3, and TYK2). TG101348, a specific JAK2 inhibitor, shows activity at high doses, but is held back by adverse effects, particularly anemia and gastrointestinal problems. This seems to afflict many of the specific JAK2 inhibitors.
Incyte’s ruxolitinib is well ahead of the pack; management anticipates a launch in myelofibrosis by the end of this year. They have completed two randomized Phase III trials: a 24 week placebo controlled US trial and a 48 week European trial comparing ruxolitinib to best of care. Only top line data was released for these trials, saving crucial data for presentation at ASCO later this June. Both trials have met their primary and secondary endpoints.
Without disclosing much information from the Phase III trial, the only useful data comes from the Phase II results. Management suggested data between the trials were on par, speaking specifically to the 15mg dose cohort from the Phase II. This suggests ruxolitinib showed an excellent safety profile, with only single digit percent grade 3-4 thrombocytopenia and anemia, with little or no non-hematologic adverse effects.
YM Biocience’s (YMI) CYT387 has shown efficacy on par with ruxolitinib, though so far only in a small, Phase I/II trial. Not only that, but it has been shown to improve anemia symptoms with an anemia response rate of 58% based transfusion independence. The mean duration of response currently stands at six months. If this holds out, the compound could potentially be best in class; it is even dosed once daily compared to the twice a day dosing for ruxolitinib.
CYT387 may have a significant advantage over its competing JAK inhibitor, but it also has some serious liabilities. Unlike ruxolitinib, CYT387 has shown some non-hematologic adverse effects- nothing as severe as TG101348, et al - but not quite as clean a toxicity profile. There are signs of both gastrointestinal and liver issues.
Another issue is time, while Incyte plans on launching its drug this year, CYT387 will likely not reach the market until 2015. Incyte is already conducting patient and physician education (though that paves the way for YM Biosciences as well) and intends on hiring managers for its sales force this quarter. In the absence of competition, ruxolitinib will likely be used in the majority of high-risk and intermediate-2 level myelofibrosis cases. 74% of patients in Incyte’s Phase II trial were from the high-risk group while 17% were from intermediate-2.
Most analysts think of ruxolitinib as a drug for alleviating constitutional symptoms such as enlarged spleens. The company is out to change this view through continued trials intended to show a disease modifying effect for the drug. Two-year overall survival of 84% from the continuing Phase II trial points to a possible improvement in survival over historical figures; high-risk patients have a median survival of about two years and intermediate-2 patients, four.
If and when CYT387 is approved, the market will not necessarily become suddenly divvied up between the two drugs as some analysts have suggested, with non-anemic patients on ruxolitinib and anemic patients on CYT387. This is because neither drug is likely to be used alone. They may be paired with prednisone, or an IMiD such as pomalidomide to boost blood cells. Or they may be used in conjunction with a stem cell transplant.
In my view, because ruxolitinib is so well tolerated and is the first to market, it will find widespread use as doctors experiment and discover the best treatment options for their patients. Still, there will be patients who do not respond to the drug or cannot tolerate it, and some patients will prefer the convenience of a once-daily drug. Market share will therefore overlap.
Only actual usage will tell which drug is truly better. Additional data at ASCO is unlikely to make that clear. For now, CYT387 and ruxolitinib simply appear to be the two best, and that’s all I need to know.

http://seekingalpha.com/article/264746-incyte-and-ym-biosciences-in-race-to-market-strongest-jak-inhibitor
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