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Novel Agent IMG-7289 Appears Well Tolerated in Patients With Myelofibrosis

Danielle Ternyila
Published Online:2:47 PM, Thu October 17, 2019
Kristen M. Pettit, MD
Kristen M. Pettit, MD
To date, there are only 2 FDA-approved therapies available for the treatment of patients with myelofibrosis (MF), including JAK inhibitors ruxolitinib (Jakafi) and fedratinib (Inrebic). However, in August 2019, the FDA granted a fast track designation to the novel agent IMG-7289 for the treatment of patients with MF.

IMG-7289 is a lysine-specific demethylase 1 (LSD1) inhibitor, which is important for the formation of specific blood cells in the bone marrow that drive the development of MF. In preclinical trials, this agent demonstrated in vivo efficacy as monotherapy as well as in combination with other drugs across a number of myeloid malignancies, including myeloproliferative neoplasms (MPNs) like MF, essential thrombocytopenia (ET), and polycythemia vera.

According to data from a phase I/IIa clinical trial, IMG-7289 is well tolerated in patients with intermediate- to high-risk patients with MF who are resistant or intolerant to the approved JAK inhibitors. A preliminary analysis of the trial demonstrated that IMG-7289 induced a reduction in spleen size in 66% of evaluable patients, as well as a ≥50% reduction in symptom scores in 56%.

This trial has been expanded to a phase IIb trial (NCT03136185) and will use a modified dosing schedule to safely optimize the efficacy of the drug in patients with MF. The trial is currently enrolling across institutions in the United States, United Kingdom, and European Union.

In an interview with Targeted Oncology, Kristen M. Pettit, MD, assistant professor at the University of Michigan, discussed the data supporting the FDA’s fast track designation of the novel agent IMG-7289 for the treatment of patients with MF.

TARGETED ONCOLOGY: What was the rationale for evaluating IMG-7289 in patients with MF?

Pettit:
IMG-7289 is an interesting novel epigenetic therapy for MF. It inhibits the enzyme LSD1. LSD1 is a specific histone demethylase, so it modifies chromatin by removing methyl groups specifically at histone 3 and lysine 4, which then has various effects on gene transcription.

We know that LSD1 acts as a key regulator of hematopoietic cell differentiation, and it’s essential for differentiation specifically of mature megakaryocytes, which play a key role in the pathogenesis of MF. We know that LSD1 is overexpressed in various malignancies, including MPNs like MF. This study is the first time that a drug with this mechanism of action, of LSD1 inhibition, has been tested in patients with MPNs.

TARGETED ONCOLOGY: How does IMG-7289 fit into the treatment landscape for MF?

Pettit:
We currently have 2 drugs that are FDA approved for MF. Ruxolitinib is a JAK1/2 inhibitor, and now we have fedratinib, which was just approved in August 2019, which is another inhibitor of JAK2 and various other kinases as well. Both ruxolitinib and fedratinib can give improvement in symptoms and/or spleen size in patients with MF. However, more than 50% of patients will not have an adequate response, and even among those patients who do respond well, about half of them will lose that response within the first few years. For those patients who do not respond to these agents or who lose their response overtime, we know that their outcomes are dismal. Most patients with MF will find themselves in this position at some point in their course, so it is really important area of unmet medical need and an area where we really need novel therapies with completely different targets, such as IMG-7289.

TARGETED ONCOLOGY: Could you discuss the data that supports the FDA’s decision to grant IMG-7289 a Fast Track designation for MF?

Pettit:
Our last data cutoff point was March 1, 2019, and as of that point, we had enrolled 16 patients. What we have seen so far is that IMG-7289 appears to be quite safe and well tolerated. The most common adverse event has been taste changes in 6 out of those first 16 patients. We saw fatigue in about a quarter of patients, nausea in about a quarter of patients, and thrombocytopenia, as expected given the mechanism of action, but no major bleeding events.

As of that March 1, 2019, cutoff date, we had 9 patients that were evaluable for responses, and for those patients with evaluable responses, they received 12 weeks of IMG-7289. Of those 9 patients, 6 had a slight reduction or stabilization in spleen volume, although those reductions were modest. None had met the standard cutoff of 35% spleen volume reduction to call it an objective response, but interestingly, symptom improvements were quite encouraging with the drug. Using the MPN10 symptom assessment tool, all patients, 9 out of 9, had some degree of symptom improvement. Five out of those 9 patients reported that their symptoms were improved by 50% or more, so that was really encouraging.

We are very excited to see what effects the drug will have when we use it longer term. For example, if spleen sizes and symptoms will continue to improve further overtime and also to see what sort of effect the drug will have on bone marrow fibrosis, mutant allele burden, and cytokine profiles.

TARGETED ONCOLOGY: What does the toxicity profile look like for IMG-7289?

Pettit:
Overall, it is quite well tolerated. It’s an oral once-daily drug, so it is easy for patients to take. As I mentioned, taste changes have been 1 thing we have seen, although in my anecdotal experience, symptoms seem to improve for patients overtime. Nausea and diarrhea have been seen but are infrequent and seem to be easily controlled. Fatigue is common, but that is also common among this patient population when untreated as well. Thrombocytopenia is not unnecessary for the mechanism of action for this drug, but as I mentioned, there haven’t been any major bleeding events seen to date. We think overall, IMG-7289 is a well-tolerated agent.

TARGETED ONCOLOGY: What are the next steps for this agent?

Pettit:
The phase II portion of this study is open and enrolling at sites in the United States, United Kingdom, and European Union. We are also planning for a study of IMG-7289 in a related disorder, ET, as well; this trial has not yet opened, but it is in development.

TARGETED ONCOLOGY: How do you see the treatment landscape of MF evolving over the next couple of years?

Pettit:
I think we are in desperate need for new treatments that can stop the progression of MF and also new treatments that can improve clinical signs and symptoms of the disease. Most importantly, we need to improve quality of life for these patients. I think drugs like IMG-7289 seem to be helping patients with MF feel better and live better, and I think those are going to be important drugs to work into the treatment landscape of MF, perhaps even in combination with other agents as well, such as JAK inhibitors.

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