Myelofibrosis Special Report
RUXOLITINIB ON TRIAL
By Zhenya Senyak
The story started long before the American Society of Clinical Oncologists gathered in Chicago.
It started four years earlier inTexas and Arizona and 153 different locations where patients, always sick, sometimes dying would swallow a single small pill every day. They were regularly driven from their homes to their local medical center to get pricked and poked, examined and sent back home to hope for the best.
In the whole history of myelofibrosis hope was in very short supply.
And then word leaked out. At first there was only a rumor of success and then the appearance of scientific abstracts, recruitment announcements for new clinical trials. Finally, last month, the story exploded across the Internet .
There is a treatment for myelofibrosis.
Where once there was nothing, now there will be something.
At the acute, devastating end of the myeloproliferative spectrum, MF usually means shortened life expectancy with some intense suffering along the way. As the marrow becomes fibrous and shuts down, blood production moves to new areas. A bloated spleen, thick with new and stored blood, restricts patient movement and appetite, a flood of poorly understood proteins often causes intense itching, bone pain, anemia, night sweats and mind-numbing fatigue.
At advanced stages, those suffering from myelofibrosis begin the process of cachexis, a wasting away syndrome of lost weight, lost muscle mass, and apathy. Eventually, some patients progress to acute myeloid leukemia but the usual cause of death is the crushing effect of myelofibrosis itself.
There is no approved therapy and only limited symptomatic relief.
The only cure for MF is a risky stem cell transplant and that option is only open to the relatively young and healthy.
The rise of hope
There were some signs that hope was on the way. In 2010, the prestigious New England Journal of Medicine published a report on those 153 patients. They had been taking a drug called INCB018424. The study was supported by Incyte Corporation and managed jointly by M.D. Anderson’s Srdan Verstovsek, the report’s lead author and Mayo Clinic’s Ruben Mesa. It was a dose escalation study of yet another JAK inhibitor.
But this time the results of the 14 month study were extraordinary – reduction of spleen volume by an average of over one-third and a 50% overall improvement of myelofibrosis symptom scores.
An open study like this may be promising but it doesn’t prove much to the United States F ood and Drug Administration that approves new drugs based on hard data derived from rigidly controlled clinical trial. The stage was set.
Incyte made the mega-million dollar decision to support two large scale Phase III clinical trials, one in theUnited States, one in Europe. These were the COMFORT (Controlled MyeloFibrosis study with Oral JAK inhibitor Treatment) trials. COMFORT I, the American trial, ended up accruing 309 patients. COMFORT II, inEurope, 219 patients.
Two basic questions would now be answered with scientific clarity. How effective is the drug – now called Ruxolitinib 424 — when matched against a placebo in a blind study? ( In a blind study patients are divided into two groups, each receiving identical looking pills, neither group knowing whether its pill contains the medication or not.) The other question: How effective is the drug compared to the Best Available Therapies, the so-called BAT drugs.
Some quantitative criteria were set up. How much would the spleen shrink, how well would the drug group compare with the placebo or BAT group in reduction of symptoms according to the Myelofibrosis Symptom Assessment Scale. With that, the trial, lasting a little under a year, began.
Back in Chicago
The results formally announced in Chicago at the ASCO conference the first week of June, 2011, were unequivocal. Ruxolitinib was able to stall the rampaging JAK clones, shrink the spleen, and dramatically improve symptoms of myelofibrosis. Incyte filed a New Drug Application with the FDA and asked for fast track approval. It is possible Ruxolitinib will be available for Christmas. But Christmas came early for most patients in COMFORT I and II, many of whom started their trial near death and completed it with a new lease on life..
The Official Results
Both COMFORT trials enrolled high risk MF patients (309 in theUS, 219 inEurope) divided into two arms. In theUS, one arm received Ruxo, 15mg or 20mg depending on platelet levels, the other was essentially untreated, receiving only a placebo.
In Europe, a BAT (Best Available Therapy) drug was given to one arm, Ruxolitinib to the other. The mix of drugs in the BAT arm, including several considered toxic in theUS, was weighted toward commonly used hydroxyurea (47%). Only 4% of the patients received interferons. No Pegasys was included
Despite the design differences, results were generally similar.
Virtually all patients in the COMFORT I Ruxolitinib arm showed some degree of spleen size reduction with 41.9% of patients achieving the targeted end point, a minimal 35% reduction in spleen volume. And nearly half of all patients on Ruxo reported a 50% improvement in symptom burden and quality of life
The results were similar although not so overwhelming in the European version of the trial, reported by Dr. Alessandro Vannucchi of theUniversityofFlorence. While none on the BAT arm of the trial experienced reduction of spleen volume, 28% of patients receiving Ruxo did reach the 35% target reduction. Reduction of severe symptoms and improvement of quality of life was reported by 31.9% of Ruxo participants and none of those on the BAT arm of the trial.
In both COMFORT I and COMFORT II, results were achieved regardless of JAK2 mutation status.
As promising as these results are, the sobering truth is this is the beginning of the battle to eliminate MF, not the end
Robert Rosen, founder of the MPN Research Foundation, considers Ruxolitinib “a huge step forward. It’s no small thing to be the first effective drug for myelofibrosis.” For Rosen, whose MPD Research Association acted as both investor and incubator for scientists working to convert the newly discovered JAK2 mutation into effective drugs for MPN patient, the entry of Ruxolitinib into the FDA approval process is a vital first step. .”We still have a long way to go,” says Rosen,” but the intense level of activity in new drug development, the investigation of new mechanisms of action, and multiple compounds in various stages of the drug development pipeline suggest an unforeseen level of progress.”
` As we go more deeply into this Special Report — and provide supporting data, links and charts to clip and share with our hematologists – the dimensions of this achievement become clearer. Along with celebration, however, there are sobering elements to this astounding success. There are those who didn’t survive, there are failures along the way, side effects to consider and a long road ahead before myelofibrosis can be said to be under control.
What does it mean?
Ruxolitinib can reduce spleen volumes. Everyone on Ruxo got some reduction and some saw complete recovery of normal spleen volumes. Four out of 10 MF patients who took it in the US saw their spleen reduce by more than a third in volume. In Europe, a little better than one out of four patients got those results..
Splenomegaly is not only one result of marrow failure, it is itself responsible for many life-altering symptoms: inability to eat or breathe normally, exercise, sleep or fulfil other normal daily functions.
With Ruxo, nearly half of all patients reported a 50% improvement in symptoms and improvement of quality of life, Then there are those on the placebo or BAT arms taking alternative drugs or none at all. They showed no reduction in spleen size and worsened overall condition. That’s us, MF patients in the pre-Ruxo world.
No free ride
. Generally, JAK2 inhibition is no longer seen as a potential cure for MF but rather one of several approaches that might be taken to attack what is a complex blood cancer. Ruxolitinib, however, did not set out to inhibit the mutant clone but impacted a much broader swath of territory.
If a drug can help you, it can hurt you. Ruxo can help and it carries negative impacts as well. It attacks the JAK2 mutant clone not with a laser guided missile but a shock and awe carpet bombing of the JAK 1 and 2 kinases and the JAK-STAT pathway. Impacting this cellular signaling link – see the sidebar on the JAK STAT pathway – suppresses the marrow, worsens anemia, lowers platelet counts and may well have other adverse effects. For those with MF already suffering from compromised marrow, anemia and thrombocytopenia, this is bad news. The study did show blood counts rebounding and hemoglobin rising to former levels after a few months on the trial. Lowering of platelets continues to be a problem since those with MF and very low platelet counts are not candidates for Ruxo. Verstovsek is confident many response issues can be safely treated at a clinical level. “We can manage these issues and balance toxicity with efficacy,” he told MPNforum, “by calibrating dosage.”
Why invest big bucks in MF anyhow?
In the carefully calibrated dance between Business and Science, patients with myeloproliferative neoplasms stand as poor relations, spectators at a festival honoring major diseases and blockbuster drugs. And among the MPNs, those who are last in line, least numerous and most in need, are those with high risk advanced myelofibrosis.
Clinical trials are expensive. We were told the numbers aren’t made public – “We haven’t given this sort of guidance in the past…” Drug companies are not compelled to tell us how they arrived at the enormous sums claimed necessary to bring a new drug to market.
An Incyte spokesperson did quote a report that might be illuminating: “Finding new cures is an extremely expensive and risky proposition…Estimates about the costs of developing a new drug vary widely from about $800 million to nearly $2 billion per drug. …Recently Pfizer announced that it is investing $800 million just for a set of Phase III trials for a single drug.”
Seriously, who is going to spend $800 million to serve a patient population of a few thousand in the US when insurance might not cover the prescription anyhow?
As MF patients, hat in hand, we can be grateful for any product promising symptomatic relief. But, considering our small numbers and the huge required investment, it is reasonable to wonder at the corporate strategy that would put so much capital in play when there are competing products in the pipeline, and several promising genetic therapies being explored.
Paul Friedman, president and CEO of Incyte, is up front about it. “There was a list and MF was on the list. It seemed the fastest road to market since there was no available therapy for a serious disease. ” Another disease on that list has much greater market potential. It turns out that the JAK STAT pathway is significant to treatment of rheumatoid arthritis, one of the major diseases afflicting ever aging populations. (And that same pathway is involved in gout and psoriasis, as well. where an offshoot of INCB18424 is being marketed as a cream “with spectacular results.”)
While there might be 18,000 MF patients in the United States– and only a subset of those would be advanced enough to qualify for Ruxo therapy — there are over 1.5 million people with rheumatoid arthritis and another 5 million with such related rheumatoid diseases as fibromyalgia and gout in the States. The worldwide market is orders of magnitude larger.
So it’s not about us. Corporate strategists might be sympathetic to the plight of victims of advanced MF but they’re also after much bigger fish and we’re just swimming in the same pond. In a very strange way, we just lucked out.
To have a shot at the RA market, Incyte needed capital, partners, product development, and recognition. In the course of proving its bio-engineering and drug marketing capabilities, Ruxolitinib helped bring all that about.
For some, it is all about us.
For front line hematologists, scientists in clinical practice who specialize in the MPNs, and those who further devote their lives to research and the care of myelofibrosis patients, we are the bottom line.
And they are both relieved and excited about Ruxolitinib.
“For the first time we have a treatment (for MF),” said trial investigator Dr. Claire Harrison of Guy’s and St. Thomas, London “that meaningfully reduces spleen size and addresses the burden of disabling symptoms.”
“It’s an extraordinarily successful study, “said Srdan Verstovsek, “in terms of reducing symptoms…shrinking the spleen. We have things to work on, combination studies to block the pathway, combine maybe with Pegasys, thalidomide or lenalidomide. We’re working on quite a few. And we have to do a study on patients with low platelets, find a way to get them this therapy. I think we have to accept the drug is eliminating symptoms not curing MF. But given such a degree of suffering and debility, the drug is valuable.”
Verstovsek also sees Ruxo as useful in preparing MF patients for bone marrow transplant. “Often when patients arrive for BMT they are in such terrible condition that the odds are against them. We can improve that, improve their nutrition and help them get more fit before starting that process.”
Will Ruxo succeed as a frontline therapy for MF and other MPNs?
Clinical trial results and efficacy in the field are necessary but not sufficient to assure Ruxolitinib of success. The jury will remain out on that one beyond the anticipated December FDA approval date. There are unknown marketing and scientific pitfalls ahead, long-term studies of survival and durability of response that will building on on-going data from the trials. And then there’s the issue of acceptance of the drug in clinical practice and insurance reimbursements. Finally, although Ruxo has a good headstart, there’s real competition just over the horizon.
A final note
As MPN/MF patients we don’t have many options. We can only wait to see how this part of the amazing Ruxolitinib story plays out. The men and women who worked on the development and testing of this drug already have an achievement beyond the balance sheet. The history of myeloproliferative disease will credit them with creating not an oral JAK inhibitor drug but the first effective therapy for advanced myelofibrosis.
With any luck at all, we too will be part of that history.
© Zhenya Senyak and MPNforum.com, 2011. Unauthorized use and/or duplication of this material without express and written permission from this blog’s author and/or owner is strictly prohibited. Excerpts and links may be used, provided that full and clear credit is given to Zhenya Senyak and MPNforum.com with appropriate and specific direction to the original content. This is how I remember the first weeks after the arrival of a new
group of hospital house officers. Things may have changed and only retired nurses and hospital personnel may remember. This month*s corner is for them. My other two readers may wonder what I*m braying about, but there are other columns and serious MPN oriented articles for them in
this issue. I*m not bashing new doctors. I used to be one myself and probably more callow than most.
Summer*s over and change is in the air. Outside the
hospitals the leaves are turning and the days and nights are comfortably
cool and work goes easier. Inside hospitals, things are again going
smoothly at nurses* stations, pharmacies, records typing pools, clinical
parking garages and telephone switchboards.They have once again survived
another bout of the dreaded Hospital Summer Virus (HSV).
The trouble begins annually in July and only begins to
wane around Labor Day or beyond. Now things have once again returned to
blessed normalcy. God is in his heavens, Congress is in recess and the creek we were up without a paddle has receded. In other words the hospitals are
functioning smoothly and among the personnel there is much less
muttering, sighing and taking of excessive sick days. Hallelujah!
Back in early July the annual onslaught of June*s graduated,
licensed, certified or whatever mark of distinction was appended to the
new and unimproved members of the afore-mentioned departments began.They quickly wreaked their destructive side effects on the wards, not to mention the patients. That*s HSV.
>>clinical pearl>> Experienced patients try never to be voluntarily
admitted to a hospital in July.)
Studies show that the most infectious carriers of HSV are the newlyminted house officers, conscious of their shiny new (read dangerous) MD*s or DO*s with the ink still wet on their sacred diplomae (or is it diplomas). The regal chief Residents and Fellows transferring from institutions they claim are more famous, who always have a better way of doing things also carry the HSV virus.
What are the symptoms and signs of HSV? They can be severe, but
fortunately the disease is self limited (that is if we stay out of Mother Nature*s way in her efforts to heal). Every hospital suffers differently, but always the suffering and the burden to teach the fledgling house staff and ameliorate the symptoms of HSV falls mostly on the nurses.
Symptoms and Signs of HSV:
1. Three pages of orders for nurses to copy. Often another page is added later on the same day.
2. Twenty PRNs ordered for each patient*s every contingency from a hiccup to dandruff. As if the nurses had never heard of a glass of water, a back rub, bathroom privileges or an enema.
3. Newly important doctors make ward rounds getting in everybody*s way
at seven, three and eleven. always just in time to interrupt nurses* narcotic and drug tally, nurses* report, patients* baths and the arrival of food carts. (old hands and house officers with nurse spouses know better than to show up at these forbidden hours).
4. The young single male doctors soon learn to box
sheets, serve trays,collect urine and draw blood for a female nurse, aide, dietitian or lab.tech. whom they fancy and want to assure they will get off-duty on time.
The reversed gender approach happens less often or at least is not
so obvious. Anyway nowadays, so I*m told by my wife, doctors marry doctors,
nurses marry nurses and so on, sparing a few head & heart aches. Abnormal hormones may circulate in some patients* plasma, but certain strong ones run rampant in young warm blooded house officers. Marriage licenses, divorce papers, positive pregnancy tests affirm these clinical trials. Most times happiness results, but sometimes there are broken hearts.
5. Two thousand word progress notes are dictated daily, some days twice,for the records department to type and type …and type some more pages that nobody reads. Good job protection for the typists and the electronic records industry, but such a pain for everybody else.
6, A bewildering soup of jargon, puzzling acronyms and unintelligible abbreviations from other hospitals and institutions suddenly appears in the medical records. ex; how many acronyms are there for a big benign prostate? BOP?, BPH?, ???.
7. A mixed bag of weights and measures, chemical and brand names all written in Latin or Greek or something vaguely suggestive of Sanskrit appears on order sheets or verbally ordered or dictated in the unintelligible variations of English that emanate from well known universities.
8. Scissors, stethoscopes, pens, cell phones, small change, phone books, etc. are *borrowed* from nurses and never returned without gentle persuasion.
9. Drugs and formulations are ordered that no self respecting pharmacist has ever dispensed or heard of since her/his pharmacy school days.
10. DNA & serum copper tests are ordered for an emergency
appendectomy for an otherwise healthy patient, stat at 3 a.m. on the weekend.
11. Stale doughnuts are offered in failed attempts to
bribe long suffering records librarians in lieu of getting medical records up to
date and on time.
12. Chief of staff*s parking space is taken up by a VW camper. Patients*
wheel chair entrance is blocked by a motorcycle with a guitar, a half consumed donut and a Red Sox cap, plus a pilfered box of bandaids, six new hospital towels, a dozen hospital diapers and a package of peri-pads, all resting on the seat.
14. Telephone operators are awakened at 3 a.m. by a
house officer*s tearful or angry spouse with much sobbing or growling. “Please
let me talk to Doctor Jane/Jim Jones. She/He said She/He would be home soon and it has been over three hours. Oh, the worry and grief …and suspicion.
Other iatrogenic hospital viral syndromes occur in July. The differential diagnosis is long and each hospital is different, but the SHV syndrome is so widespread that I*m sure all our Nurses, Pharmacists, Records Staff, Parking Attendants and Telephone Operators will recognize it instantly.
Anyway, as I wrote many parentheses, comma faults and *run-on sentences* above, it*s Fall and the SHV syndrome has abated. By
this time the nurses have taught well and the trained and indoctrinated
house staff understands the real pecking order and power structure.
Happily, the hospital wards are running smoothly once again. So this is enough blather (too much?) until next month when I might discuss some of the other non-clinical goings on around hospital wards that took place back in the
day, Interesting things happened that patients and administration never knew about. Reckon I better not. Some of my peers are still alive and they might subscribe to MPNforum. :)
© Arch M. and MPNforum.com, 2011. Unauthorized use and/or duplication of this material without express and written permission from this blog’s author and/or owner is strictly prohibited. Excerpts and links may be used, provided that full and clear credit is given to Arch M.and MPNforum.com with appropriate and specific direction to the original content.
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