New Drug for Myelodysplastic Syndrome Advances Towards FDA Approval — What is it, Who Can Benefit & What You Need to Know

Although reducing how often patients with MDS need to undergo blood transfusions would be a major advancement, like all cancer therapies, there is the potential for side effects. Here, we discuss what Imetelstat is, how it works, who can benefit from the medication, what the side effects are, and what to ask your doctor.

What is Imetelstat?

Imetelstat, also referred to as GRN163L, is a drug that targets a part of cells known as telomerase — and is one of the first telomerase inhibitors to be involved in clinical trials. To understand the significance of this medication, how it works, the benefits of Imetelstat, and the risks/side effects of this medication we need to take a quick detour to understand what telomeres are and what telomerase does in your body.

The ends of DNA are called telomeres and are made up of a series of repeating code that is not used in normal cell functioning. When a cell undergoes division, there is a natural process by which the very ends of the DNA, or telomeres, are shortened. This means, with every cell division a tiny portion of the DNA is lost in these telomeres.

Telomerase is a special protein (known as an enzyme) present in some cells that can lengthen the ends of DNA, or telomeres. Telomerase is not present in most normal cells, but can be important for certain cells that undergo replication frequently — including stem cells. Some cancer cells, because they divide and replicate so frequently, also have telomerase to prevent shortening of the ends of their DNA.

During the DNA replication process, at some point the ends of the DNA will run out and the cell will not be able to replicate. The enzyme telomerase helps overcome this process by adding new DNA to the ends of the gene allowing a cell to continue to replicate. As you can imagine, if a cancer cell has this ability or enzyme, it gives the cell ability to grow for a longer time and thus cause more damage to normal healthy tissue.

The reason this explanation is important is that certain normal cells, such as stem cells, need telomerase and this ability to function properly. There has been pause in the scientific community on the use of drugs that specifically target this enzyme given its vital role in the cell cycle.

Imetelstat is a telomerase inhibitor and binds to telomerase in order to reduce its ability to lengthen the ends of DNA (telomeres). By doing this, it attacks certain cells with active telomerase that are dividing and replicating frequently. Prior studies performed in labs at Johns Hopkins University, demonstrated that Imetelstat works to stop telomerase function and growth of certain cancer cells.

The Approval Process

Imetelstat, just like any other medication that is prescribed or given to a patient, has a specific guideline for use which is developed by the manufacturer of the drug. This guideline is then approved by the FDA. Often, insurance companies will then cover the use of medications based on their FDA approval.

In order for a medication to get approved by the FDA, rigorous testing needs to take place which often has multiple steps and can span over years.

Initially, when a new drug is developed it undergoes laboratory and animal testing to answer basic questions about its efficacy and safety. Once the drug is felt to be adequately useful and safe it moves to the next phase of clinical research where the drug is used on people to ensure it is safe and effective.

During this time severe toxicity or side effects that occur are recorded and followed. A study for a new drug can be discontinued at any time if the side effects are felt to be too common or severe, or they outweigh the benefit of the drug.

One of the last phases of clinical trial testing is called a phase 3 clinical trial. Here they compare a new drug to the current standard of care to see if it is better than what we already have. A phase 3 clinical trial often takes place at multiple hospitals across the country (or several nations) and involves hundreds of patients.

Once all of this testing is completed and the new drug shows improvement in patient outcomes with acceptable toxicity, they can be submitted to the FDA for review and approval.

Imetelstat went through all of this testing and is now filing for approval by the FDA. However there were some concerns about the side effects of the drug. An FDA Advisory Committee just voted 12-2 that the benefits do outweigh the risks.

When is Imetelstat Used?

Imetelstat is used in patients in with myelodysplastic syndrome, or MDS, which is a group of disorders of the blood cells in your bone marrow. When the cells in your bone marrow that produce new blood cells become defective, it results in an abnormal or low numbers of cells.

People can have a number of side effects depending on which cell types are effected. Symptoms can include fatigue and shortness of breath, weakened immune system with frequent infections, or excess bleeding to name a few. Treatment is often aimed at slowing the disease course and addressing symptoms. Treatments often include regular blood transfusions, medications to stimulate the cells in the bone marrow to grow, and immune system inhibitors.

Imetelstat has been approved for use in adult patients with low-to-intermediate-1 risk MDS who are transfusion dependent and have not responded or stopped responding to erythropoiesis-stimulating agents (medication used to boost production of red blood cells).

Essentially, if you have a low-intermediate-1 risk MDS and have low blood counts which are not responding to medication and require regular blood transfusion to keep your blood counts up, Imetelstat helps to reduce how often you need to get blood transfusions.

What Were the Trial Results

In a phase 3 clinical trial called IMerge, Imetelstat was tested in patients with low-intermediate-1 risk MDS that were requiring blood transfusions and not responding to medication. 178 patients in 17 countries were included, with 118 patients assigned to receive Imetelstat and 60 to receive placebo.

The main goal of the study was to see how many patients in each group (Imetelstat vs. placebo) could go without a blood transfusion over the course of eight weeks. The study found 40% of patients that received Imetelstat went at least eight weeks without receiving a blood transfusion, while only 15% of patients receiving the placebo medication made it to eight weeks.

What are the Side Effects?

As discussed above, there were concerns over the use of a telomerase inhibitor in the clinical setting.  A

In the clinical trial, although there was a benefit of Imetelstat, with more patients able to go longer without the use of blood transfusions, the risk of side effects was much higher.

Although there were no deaths from the medication, 91% of patients receiving Imetelstat (compared to 47% placebo) has serious adverse effects which required treatment or hospitalization. The most common serious adverse events were neutropenia (a low count of a certain type of white blood cells) in 68% and thrombocytopenia (low blood platelet count) in 62% of Imetelstat patients.

Despite the higher risk of adverse events, the experts of the FDA advisory committee thought the benefits gained outweighed these risks.

Bottom Line

Although the trial did demonstrate a reduction in blood transfusions, it had a significant increase in toxicity with severe events including neutropenia (decreased white blood cell count) , thrombocytopenia (decreased platelet count), and hospitalizations. This will pose a challenge for both providers and patients the risk versus benefit of taking this medication.

Questions to Ask Your Doctor

When Imetelstat becomes available, here are some questions you might consider asking your doctor about the new treatment option.

• What is the benefit of reducing blood transfusions when treating myelodysplastic syndrome?
• When should I consider taking a medication like Imetelstat?
• Are there any side effects of Imetelstat that pose a threat to my health knowing my individual health factors?
• What were the most severe side effects from Imetelstat?
• When will Imetelast make its way into clinical use and am I a good candidate?

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