Imetelstat is a "first in class" drug
Interestingly, First-in-Class and Rare Disease Drug Approvals Dominated the FDA in 2015
"FDA highlighted noteworthy first-in-class products that were recently approved, including: Merck’s Bridion (sugammadex), to reverse post-surgical neuromuscular blockade caused by certain kinds of anesthesia; Pfizer’s Ibrance (palbociclib), to treat advanced (metastatic) breast cancer and Boehringer Ingelheim’s Praxbind (idarucizumab), to reverse adverse anticoagulant effects caused by the blood-thinner drug Pradaxa (dabigatran).
Since the new international MF clinical trial is using patients whose condition is rapidly failing despite the JAK inhibitor by INCY named Jakafi... I wondered what percent of patients had also failed JAK Inhibitor treatment prior to their enrollment in the highly successful Imetelstat Mayo Study.
According to Tefferi's data the answer is **57.6%** [ "Previously Treated 26 (78.8%) Median # of Prior Treatments (range) 2 (1–6) Prior JAK inhibitors 19 (57.6%)"]
This is strong indicator that J&J/Geron used to guide them in designing the current trial.... namely
"Study to Evaluate Activity of 2 Dose Levels of Imetelstat in Participants With Intermediate-2 or High-Risk Myelofibrosis (MF) Previously Treated With Janus Kinase (JAK) Inhibitor"
Texas I was skeptical but you are correct as on page four of Janssen's Jan 15th presentation
"Hematologic Malignancies: One of Three Areas of Focus Our Goal: Transformational, Comprehensive Portfolios"
F.D.A. Regulator, Widowed by Cancer, Helps Speed Drug Approval
In her struggle with cancer and ultimately her death in November, Ms. Pazdur had a part, her husband and a number of cancer specialists now say, in a profound change at the F.D.A.: a speeding up of the drug approval process. Ms. Pazdur’s three-year battle with cancer was a factor, they say, in Dr. Pazdur’s willingness to swiftly approve risky new treatments and a passion to fight the disease that patient advocates thought he lacked.
I have a much greater sense of urgency these days,” Dr. Pazdur, 63, said in an interview. “I have been on a jihad to streamline the review process and get things out the door faster. I have evolved from regulator to regulator-advocate.”
It is a Surrogate Endpoint Leading to both Accelerated approval or Breakthrough Status
The FDA states that “In 2012, Congress passed the Food and Drug Administration Safety Innovations to allow the FDA to base accelerated approval for drugs for serious conditions that fill an unmet medical need on whether the drug has an effect on a **surrogate** or an intermediate clinical endpoint.”
The FDA further states"A surrogate endpoint used for accelerated approval is a marker - a laboratory measurement, radiographic image, physical sign or other measure like transfusion independence that can predict clinical benefit, but is not itself a measure of clinical benefit. Surrogate endpoints are useful when it takes a long time to see a real clinical outcome endpoint like survival time."
Anemia is the most relevant clinical problem for the majority of patients with MDS. More than **90%** of MDS patients are anemic at the time of diagnosis, and severe anemia is observed in about 60% of cases. Once anemia is symptomatic, red blood cell (RBC) **transfusions** are the mainstays of therapy.
Frequent RBC transfusions may cause significant clinical complications, such as transfusion reactions, infection, and iron overload leading to ***shorter survival time***. After analyzing patients diagnosed with early myelodysplastic syndromes (MDS), Czech researchers from the Institute of Hematology and Blood Transfusion concluded that dependence on red blood cell transfusions has a significantly negative impact on the length of overall survival.
Their results showed that median overall survival was decreased from 65 months to 35 months in patients who required any more than two red blood cell transfusions per month.
So this tells us (and the FDA) that if Imetelstat is proven to achieve transfusion independence for patients ….this will increase survival time very significantly.
Jannsen/Geron, in my opinion chose the very best measure and the fastest path to FDA approval.
The same Dr. Tefferi who is reporting the excellent results of Imetelstat today and for the last 3 years also in the past reported on the dismal results of Ruxolitinib where 47 of 51 patients dropped out of Phase I/II clinical trials — because of either lack of response or serious adverse events. 18 patients (35%) died and 10% became leukemic.
Then in 2012 his study of 1000 Mayo Clinic myelofibrosis patients over a period 34 YEARS he concluded Ruxolitinib (Jakafi) is somewhat usable for only about 20% of primary myelofibrosis patients.
Clearly, based on Tefferi’s work in Blood Cancer there is an URGENT need for Imetelstat because Jakafi just isn’t up to the job.
Jakafi might not be so much a solution but more of a Band-Aid that treats only the symptoms of a chronic and inexorable disease that ultimately leads to death.
Despite the recent protestations of Jacosa stating that treating the symptoms of a disease is the “ONLY” interest to a physician or the patient suffering from MF and that disease modification, disease reversal, CRs, PRs and bone marrow fibrosis reversal is unimportant….upon even modest examination one can show how untrue this is.
The first question one could ask is why does the spleen enlarge during MF?
In many instances, the spleen enlarges in order to perform its normal functions and to compensate for loss of blood production in disease.
Examine • Extramedullary hematopoiesis in Myelofibrosis
For human fetuses blood is produced in the spleen and liver but this function is gradually replaced as the fetus develops bone marrow which takes over RBC production. Now in myelofibrosis…. Bone marrow is destroyed so the body reverts back to making RBCs in the spleen and liver in order to survive and these organ enlarge to do this …..but cause other problems in doing so.
Myleofibrosis was first described in 1879 by Heuck who reported the first evidence of marrow fibrosis and extramedullary hematopoiesis of the spleen and liver in two patients. Heuck observed with myelofibrosis, the normally spongy bone marrow becomes scarred. The end result is usually a lack of red blood cells — which causes the anemia characteristic of myelofibrosis.
“IF” a drug agent ONLY reduces the size of the spleen without replacing the RBC production enabled by a larger spleen then Harm must be done.
I think this is one of the sources of Tefferi’s frustration with Jakafi in that such palliative treatments can create a problem because treating the symptoms rather than the disease provokes a pernicious feedback loop, a dys-therapy that allows the disease to persist and to intensify. .....earfool
Bio you are correct this abstract is not a further enhancement of Lane’s data.
“Activity of the Telomerase Inhibitor GRN163L (Imetelstat) on Acute Myeloblastic Leukemia Blasts Is Enhanced By DNA Methyltransferase Inhibitors Irrespective of TERT Promoter Methylation Status”
Caroline R Cantilena et al show that high risk primary leukemias are susceptible to being destroyed by the telomerase inhibitor irrespective of the degree of methylation of the hTERTpro/Ex1 region.
Furthermore, she reports that demethylating agents can ***enhance the activity of the telomerase inhibitor***, imetelstat. These findings suggest that combination therapy of imetelstat and DNMT inhibitors may have synergistic anti-leukemic efficacy in high risk AML patients.
The graph data given was very compelling even in the absence of the complete poster and maybe Geron/Janssen will synergistically combine Imetelstat with DNMT inhibitors to enhance the activity of Imetelstat on Acute Myeloblastic Leukemia (AML) Blasts in the next couple of years.
Bio I was just reading the last Geron CC transcript and saw this about AML
"A third imetelstat abstract containing nonclinical data evaluating the activity of the imetelstat in a non-clinical model of "AML" was selected for presentation as a poster in a Saturday evening poster session. This information is also contained in a press release we issued this morning."
So AML is being presented
I'm headed to the ASH web site to find the authors and content.