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JAK2 inhibitor

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Sharmin:
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 :)

Sharmin

love and prayers:
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.

love and prayers:
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

Dori:
I am sure I was told about this during Conference 2011..

love and prayers:
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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