CPI-613 (Devimistat) + Cytarabine + Mitoxantrone in Acute Myeloid Leukemia (AML) FDA Fast Track Designation

CPI-613 (Devimistat) Demonstrates Positive Outcomes in Relapsed/Refractory Acute AML

This is a clinical trial that is designed for patients with acute myeloid leukemia (AML). They have already received prior therapy and either relapsed or refractory aml to the prior therapy. So, it's what we call salvage therapy and the design of the CPI-613 (Devimistat) study is that of the patient. It's a phase 3 randomized multicenter clinical trial.

CPI-613 (Devimistat) + Cytarabine + Mitoxantrone in Acute Myeloid Leukemia Study Design

It's a large study and the design is that they will be randomly assigned to receive either the combination of the experimental drug, CPI-613 / Devimistat in combination with Mitoxantrone and Cytarabine, two drugs that we use very regularly for the intent to treat population of acute myeloid leukemia (AML), particularly in the salvage setting or they received just chemotherapy alone, and for the chemotherapy alone, there's not really a good standard. So, we are giving different options to the physician to choose from. When is a combination of Cytarabine and Mitoxantrone the same as when they are used together with Etoposide? But the two other options are Mitoxantrone, Etoposide, and Cytarabine. The last option is what we call a FLAG, which is for Cytarabine a KRAS. The primary end point of the trial is to see if this combination can improve the response rate. Of course, key secondary end points look at overall survival, which is a key secondary end points, and safety MPKs.

Patient-Reported Outcomes of CPI-613 / Devimistat in combination with Cytarabine + Mitoxantrone in Acute Myeloid Leukemia

Patient-reported outcomes is very important to see nowadays that the quality of life is preserved in hard to treat cancers. We're also looking at that possibility. A good clinical trial to try to improve the outcome since they tend to do very poorly. Overall, again, the CPI-613 (Devimistat) trial is multicenter multinational, the target enrollment is to have 500 patients with acute myeloid leukemia (AML), but there are several interim analyses to see if things are going well, if there are no safety concerns, if there is no evidence of utility, and things like that. One is, why exactly are we doing this? And this is an interesting question because this is a CPI-613 (Devimistat) that works in a very different way than any other investigation or drug that we've used. CPI-613 (Devimistat) takes advantage of the fact that the metabolism of cancer cells in leukemia cells is different.

The production of ATP is unique to cancer cells. So, it affects the mechanism by cancer cell energy metabolism. It does not. The fact is that the normal hematopoietic cells, and that's why this Devimistat was developed in the first place. So, it is a concept that is novel and unique, and it gives a good opportunity in addition because it can be extended to other settings and there's other clinical trials in other cancers, where this is also being investigated including metastatic pancreatic cancer. For example, the next question is why CPI-613 / Devimistat in combination is with Cytarabine and Mitoxantrone and this is the reason CPI-613 (Devimistat) was first investigated. These were our colleagues from Wake Forest.

CPI-613 (Devimistat) history with Rafael Pharmaceuticals, Inc.

They developed CPI-613 (Devimistat), and then they did the initial clinical trial in phase 1 and then a phase 2 trial that suggested that the results were actually quite attractive, much higher than you would've expected. Of course, it's a phase 2, and you're comparing CPI-613 (Devimistat) to historical controls, but the results were such that we thought that it was warranted to take it to these, to this next step of a full randomized study and potentially a pivotal trial and that's why it has given designation for fast-track designation third, why this patient population salvage and the older group of salvage. They're not exactly old, but they're older than 50, not the younger population; this is where it was tested in the phase 2 context.

And not only was CPI-613 (Devimistat) effective treatments, as I already mentioned, but this combination was very well tolerated. It didn't result in any greater mortality than you would expect. So, it suggested these combinations would offer the possibility of longstanding remissions for these patients with acute myeloid leukemia (AML) and give them a better outcome. In these contexts, they have such a poor prognosis.

What Does CPI-613 (Devimistat) Mean in a Clinical Practice Setting?

CPI-613 (Devimistat) is still experimental, but what we are hoping is that it will show results. The results are the positive outcome that we expect based on the earlier clinical trial data collected and the phase 2 trial that was the genesis of this concept and that it can lead to approval.

If that is the case, then it will certainly have an effect. What do we do again? In the savage setting, we have tried so many things, and nothing really has improved the outcome, except for unique settings. For example, fleet 3 mutated. Yes, we do have the recently approved (inaudible) inhibitor (inaudible) with IDH mutations.

We have the recent approval of both IDH1 and IDH2 inhibitors. So, if they have those mutations, we have something to offer. But for all the other patients with metastatic pancreatic, who still represent a majority, we don't have anything. We just used chemotherapy, and the results are clearly suboptimal. Unfortunately, most patients do not do well after that.

So, having a good option that gives us a better probability of getting a remission, taking them to transplant, and not being eligible for transplant, giving them an opportunity to have a long-standing remission, I think that could be a game changer in the treatment of acute myeloid leukemia (AML).

FDA Grants Fast Track Designation to CPI-613 in Metastatic Pancreatic Cancer. What's Next for the CPI-613 (Devimistat) Trial?

Certainly, we want to continue enrolling in this trial and get to the analysis and hopefully good results. As I mentioned, I think that CPI-613 (Devimistat), because of the mechanism of action, is not unique to this combination, for these particular patient population, et cetera. We could start exploring other combinations, other settings, and even combining it with some of the targeted agents that I mentioned earlier, I think because of its unique mechanism of action 1 and 2 because of its good safety profile.

It lends itself to be expanded into many other indications and with many other combinations. We are all very hopeful. That these studies result in positive outcomes is most important for the patients with AML, of course, but also because then it'll give us the opportunity to expand further into these other settings.

I think it is important to emphasize that the results of phase 2 were very good and very positive and make us believe that there is a good chance that this trial will result in a positive outcome for them and positive results with possible approval. That data. It flew under the radar. It is not as well known. It's starting to get better known now that this clinical trial is out. And I think it is important to focus on these alternative pathways of affecting leukemia cells that are not specific or dependent on a given mutation.

It could potentially apply to some of the most difficult scenarios that we have. For example, patients with P53 mutated A disease or others where we don't have good treatment options. And perhaps going through these pathways may help us improve the outcome for those patients. And not only in the salvage setting but even in the frontline setting, I'd love to see this drug go to the frontline setting.

Author Credentials and Affiliations - Jorge Cortes, MD -

The Georgia Cancer Center is led by Dr. Jorge E. Cortes. Dr. Cortes joins the Cancer Center on September 1, 2019, after working at The University of Texas MD Anderson Cancer Center for 23 years.

Dr. Cortes completed his undergraduate and postgraduate studies in Mexico City before beginning his fellowship in Houston, Texas. He has been the primary investigator on over 230 grants and contracts. He has approximately 1,000 peer-reviewed original research articles to his name, as well as countless other honors for his name and profession.

Dr. Cortes will continue the Georgia Cancer Center's mission of obtaining National Cancer Institute (NCI) designation while keeping our mission of reducing the burden of cancer in the State of Georgia and around the world through superior care, innovation, and education' at the forefront of all endeavors. It gives us tremendous hope and honor to have him join our team, given his knowledge and drive to be a pioneer in developing innovative treatment options for this condition. He was also the principal investigator of the CPI-613 (Devimistat) trial.

About CPI-613 (Devimistat) (from Rafael Pharmaceuticals, Inc. News Release)

CPI-613 (Devimistat) is a first-in-class clinical lead compound of Rafael that targets enzymes that are involved in cancer cell energy metabolism and are located in the mitochondria of cancer cells. CPI-613 (Devimistat) is designed to target the mitochondrial tricarboxylic acid (TCA) cycle, a process essential to tumor cell multiplication and overall survival, or progression free survival, selectively in cancer cells. CPI-613 (Devimistat) substantially increases the sensitivity of cancer cells to a diverse range of chemotherapeutic agents in the cancer cell energy metabolism. This synergy allows for potential combinations of CPI-613 (Devimistat) with lower doses of these generally toxic drugs to be more effective with fewer side effects for patients. Combination with CPI-613 (Devimistat) represents a diverse range of opportunities to substantially improve patients' benefits in many different cancers. The U.S. Food and Drug Administration (FDA) has given Rafael approval to initiate pivotal Phase 3 clinical trials in pancreatic cancer (AVENGER 500®) and AML (ARMADA 2000), and has designated CPI-613 (Devimistat) as an orphan drug for the treating aml patients with metastatic pancreatic cancer, AML, myelodysplastic syndrome, peripheral T-cell lymphoma, Burkitt’s lymphoma, and soft tissue sarcoma. The EMA has granted orphan drug designation to CPI-613 (Devimistat) for metastatic pancreatic cancer and AML.

UPDATE - Rafael Pharmaceuticals Receives FDA Fast Track Designation for CPI-613® (devimistat) for the Treatment of Acute Myeloid Leukemia (AML) News Release from Rafael Pharmaceuticals

December 15, 2020 11:09 ET | Source: Rafael Pharmaceuticals, Inc.

CRANBURY, N.J., Dec. 15, 2020 (GLOBE NEWSWIRE) -- Rafael Pharmaceuticals, Inc. (“Rafael” or the “Company”), a leader in the growing field of cancer metabolism-based therapeutics, announced today that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation for the Company’s lead compound, CPI-613® (devimistat), for the treatment of acute myeloid leukemia (AML).

“Receiving Fast Track designation, especially during a pandemic that has created significant challenges for many trials across the globe, is a testament to the dedicated work of the Rafael team,” said Sanjeev Luther, President and CEO of Rafael. “We would not be here without the support of the FDA, our medical oncologist, our patients, and all who are invested in the hope of finding a successful treatment for this hard-to-treat cancer.”

While one of the most common types of leukemia in adults, AML accounts for only 1% of all cancers.

“This designation underscores the pressing need to find new ways to combat this aggressive disease,” said Jorge Cortes, M.D., Director of the Georgia Cancer Center at Augusta University and principal investigator on the Phase 3 clinical trial. “It brings hope not only to clinicians, but to patients who hear that they have been diagnosed.”

“We would not be here today without our principal investigator Jorge Cortes, M.D., the FDA, and leadership at Rafael who remain focused on patient care,” said Timothy S. Pardee, M.D., Ph.D., Co-Chief Medical Officer of the Company. “We are a community coming together to fight a common enemy, and I believe we are gaining ground in this battle every day.”

This announcement comes on the heels of the Company receiving Fast Track designation for devimistat for the treatment of metastatic pancreatic cancer, in November. The company has continued to reach milestones throughout the year, including the recent Orphan Drug Designation for the treatment of soft tissue sarcoma for devimistat, and the initiation of a Phase 2 clinical trial of devimistat in combination with hydroxychloroquine in patients with clear cell sarcoma of soft tissue.

About CPI-613® (devimistat) 
CPI-613® (devimistat) is a first-in-class clinical lead compound of Rafael, which targets enzymes that are involved in cancer cell energy metabolism and are located in the mitochondria of cancer cells. Devimistat is designed to target the mitochondrial tricarboxylic acid (TCA) cycle, a process essential to tumor cell multiplication and overall survival, or progression free survival, selectively in cancer cells. Devimistat substantially increases the sensitivity of cancer cells to a diverse range of chemotherapeutic agents. This synergy allows for potential combinations of devimistat with lower doses of these generally toxic drugs to be more effective with lower patient’s side effects. Combination with devimistat represents a diverse range of opportunities to substantially improve patient’s benefit in many different cancers. The U.S. Food and Drug Administration (FDA) has given Rafael approval to initiate pivotal Phase 3 clinical trials in pancreatic cancer (AVENGER 500®) and acute myeloid leukemia (ARMADA 2000), and has designated devimistat as an orphan drug for the treatment of metastatic pancreatic cancer, acute myeloid leukemia, myelodysplastic syndrome, peripheral T-cell lymphoma, Burkitt’s lymphoma and soft tissue sarcoma. The EMA has granted orphan drug designation to devimistat for pancreatic cancer and acute myeloid leukemia.

References

1. GlobeNewswire News Release - UPDATE - Rafael Pharmaceuticals Receives FDA Fast Track Designation for CPI-613® (devimistat) for the Treatment of Acute Myeloid Leukemia (AML). GlobeNewswire News Release (Press Release), December 15, 2020

2. Augusta University, Georgia Cancer Center - Leadership. Augusta University, Georgia Cancer Center, 2022