MEI Pharma is developing a new kind of small molecule epigenetic modifier in partnership with The Helsinn Group to treat acute myeloid leukemia (AML), a blood cancer that strikes mostly adults in their late 60s and leaves some patients with limited options for survival.

The drug candidate, pracinostat, is one of four clinical-stage oncology candidates in MEI’s pipeline, and was granted Breakthrough Therapy designation by the US Food and Drug Administration (FDA).

Pracinostat blocks histone deacetylase – an enzyme involved in regulating gene expression. It is being tested in Phase 3 trials in combination with azacitidine, another small molecule epigenetic modifier, which targets a different gene expression regulating enzyme and is already on the market and used for AML.

The strategy combines two drugs assaulting different gene expression patterns associated with AML in the hope of extending survival for a certain group of these patients far beyond the median 10 months they currently face.

MEI’s President & CEO Dan Gold, Ph.D., said the FDA’s breakthrough designation enabled his company to negotiate a partnership with Helsinn that ensures a faster development and commercialization timeline for pracinostat.

“When an emerging company like ours is looking to embark on a global Phase 3 trial, with the eventual goal of getting the drug approved and marketing it, there are huge financial implications that go with that,” said Gold. “Frankly that was going to be very difficult for us and we made the decision to partner.”

In addition, MEI is developing three other small molecule cancer drug candidates, including one that is being evaluated in a study intended to support a submission for accelerated approval by the FDA for relapsed and refractory follicular lymphoma. As with pracinostat, all three are aimed at validated genetic targets associated with cancer.

WuXi AppTec Communications spoke with Gold about pracinostat and the company’s other new drug candidates targeting cancer as part of an exclusive series spotlighting the inside perspectives of thought leaders on topics shaping the future of new medicines.

Gold has approximately 25 years of drug discovery and development experience. Before joining MEI he was president and CEO of Prospect Therapeutics, a mid-stage oncology company, and was founder and chief scientific officer of Favrille, another cancer drug development company. He holds a Ph.D. in pathology/immunology from Tufts University and a bachelor’s degree in biology from the University of California, Los Angeles. 

WuXi: What qualifies pracinostat for Breakthrough Therapy designation (BTD)?

Dan Gold: Breakthrough designation is a mechanism the FDA has created to give companies eligibility for certain benefits. The designation is given to drug candidates that have preliminary clinical data for serious conditions, which indicate the drug may be a substantial improvement over what is currently available.

In our case, in the disease indication in acute myeloid leukemia (AML), the median age of onset is about 67 or 68. The standard treatment involves getting a patient into complete remission with very high doses of chemotherapy and then performing a bone marrow transplant. There are, however, a significant number of patients who, either by age or other clinical factors, are not candidates for bone marrow transplant or high doses of chemotherapy. For these patients there are low dose chemotherapy options available and in general they extend the patient’s life by maybe as much as a median of 10 months.

We conducted a Phase 2 study of about 50 or 60 patients where we combined our drug, pracinostat, with one of these low dose chemotherapy options, called azacitidine. We showed we could double the historic complete remission rate and almost double the median survival in those patients. This wasn’t a head-to-head comparison, this was looking back on historical controls. We presented that data to the FDA and based on our discussions with agency officials and their review of the data they granted us breakthrough designation.

The big significance of breakthrough designation is that it’s an acknowledgement by the FDA that if your data continues to trend in that direction, it represents a meaningful improvement on treatment. But importantly, it also gives you an access channel with the FDA as you continue your development all the way through filing for approval. And it can cut down the review time by several months. It gives you access for questions to get clarifications on endpoints. So in general, it’s a very good and very helpful thing to have when you’re in the late stages of the development process.

We made the decision with our collaborators, Helsinn Group, to make survival the endpoint of the Phase 3 trial because it’s the most important outcome for these patients. For AML patients who get intensive chemotherapy there is a correlation with receiving a complete remission and survival. It’s less clear in low intensive chemotherapy. That’s why we decided to go straight for the survival endpoint.

WuXi: How does pracinostat differ from existing therapy? What is the drug’s mechanism of action?

Dan Gold: Azacitidine and another low dose chemotherapy, decitabine, are drugs that form a class called epigenetic modifiers.

Every cell in our body contains the genetic blueprints, the DNA, for instructions on how that cell should operate. And there are multiple different ways each cell modulates, controls or regulates the reading of that blueprint. One of these ways, which is a very important normal developmental strategy, is called epigenetic modification. You modify the genetic code by chemically modifying it with enzymes that are in every cell, and they are expressed at different times and at different levels in all cells.

This can greatly affect how the blueprint is read, whether it’s read at all or whether it’s read preferentially, or something in between. Azacitidine and decitabine affect the epigenetic modification of DNA.

Pracinostat is an HDAC (histone deacetylase) inhibitor, which has a different mechanism of epigenetic modification from azacitidine. The data had shown in preclinical work that when you combine these two agents, coming at epigenetics from two different directions, you have a synergistic effect. So that’s what we decided to explore with pracinostat. The data we had collected up to when we started the global Phase 3 trial with our partner, Helsinn, suggested that in people there is an apparent synergistic effect, which now needs to be further demonstrated in a controlled setting.

WuXi: What impact does the breakthrough designation have on your company?

Dan Gold: When we filed for the breakthrough designation, we had very good conversations with the FDA leading up to the designation and that led immediately to an agreement on the design and the inclusion criteria for the patients who would be treated in the global registration study – which is a randomized Phase 3 trial. Having those two things in hand – an approved trial protocol with breakthrough designation – made our discussions much more straightforward with the eventual partner, Helsinn.

At the time, when a company like ours is looking to embark on a global Phase 3 trial, with the eventual goal of getting the drug approved and marketing it, there are huge financial implications that go with that. Frankly that was going to be very difficult for us and we made the decision to partner.

WuXi: What is your overall drug development strategy?

Dan Gold: When I took over in 2010, we made the decision to focus our resources and our energies into building an organization that could build on particular skills. The skills I felt were going to be crucial, were individuals who had significant oncology drug development experience; people who had been there, done that, who would understand not just drug development, but oncology specifically, and who had actually taken a drug across the finish line.

So that’s really what I embarked on. With those people in hand we could use our connections and resources to identify compounds that were able to be acquired. That’s what led to pracinostat; and we currently have four drugs under development, one of which came from the company’s original R&D efforts (in Australia). The other three we acquired over the past few years and two are now in registration studies.

We take a focused approach, sort of a big pharma approach, before we make a decision. Our goal is to find drug candidates, and devise a path for developing them where we give the drug its best chance to succeed.  And if it doesn’t succeed, it wasn’t that we let the drug down, it was because the drug just wasn’t a good candidate, and thankfully so far that hasn’t been the case.

WuXi: What other lessons can companies learn from your drug development experience?

Dan Gold: Once we go through our evaluation process we set a very high bar. I think you have to be fairly rigorous in setting that bar and following your instincts. I mean things change, obviously. You may not have as much information once you get started, and so you might have to alter your expectations.

In general, I think, you have to be really thoughtful on what your goal is and what you accept as evidence. The hardest thing is what you accept as evidence. The truth is most of us, most companies, when you’re starting out you’re looking at your drug as it performs based on history, and history does change as well. So you do need to be pretty rigorous in your decision making process.

Another lesson I have told others, is you need to understand what your core competence is. A perfect example is that one of the drugs we acquired was being developed by a small company that had an excellent technology, a device. They were testing this particular drug, thought it was interesting and were able to license it from a larger pharma. But they had no drug development experience. They understood what their device’s capabilities were and that’s where their strengths were. But when they came to drug development, they really didn’t know where to start.

So it is important to know what you’re good at and focus on that. That’s why in our company we focus on the drug development aspect, because that’s what we are good at. It’s what we built the team around. And by being rigorous and following our own rules we continue, hopefully, to make excellent decisions.

As time passes and we move towards becoming a commercial entity, the expertise in-house will have to change. We will go out and get those excellent individuals, just like we did early on the clinical side.

WuXi: What are the other drugs in your pipeline?

Dan Gold: Pracinostat is our lead, and is wholly partnered with Helsinn.

ME-401 is our next furthest along drug, which we own outright. We recently gave a license to Kyowa Hakko Kirin Co., Ltd. for Japan.

This is a drug that is in a class of drugs called a PI3 kinase inhibitor. This is a target that has been validated. Gilead Sciences has a first generation PI3K-selective inhibitor like ours and it is FDA approved for certain B-cell malignancies.

It turns out that the PI3K delta isotype is absolutely critical. It sits in the center of all the trafficking of information that goes on in both normal and malignant B cells. It takes all the signals and integrates that information to help the malignant cell proliferate, survive and traffic into safe havens in locations in the lymph node where the cells are protected from external forces, which are trying to overcome their growth and ability to stay in those protected organs.

We have shown that our drug, on its own as a single agent, has significant efficacy or activity in patients who have various B-cell malignancies, particularly chronic lymphocytic leukemia and follicular lymphoma. These patients are in the relapsed setting. They have already been treated and have failed their prior treatments; and we reported previously that up to 80% of patients will respond to our drug. This is significantly higher than examples of PI3K inhibitors that are FDA approved or under development.

We are currently in a global study that if successful we believe will support our accelerated approval strategy, which is a mechanism the FDA has developed where you can get your drug approved on response only. If you show your drug can induce responses, particularly in late-stage settings where there is no currently approved drug, you can get approval and start selling your drug with a commitment to do a subsequent study to confirm the drug is truly active by comparing it to a standard of care. You agree with the FDA on what that study will look like for a full approval. That trial is underway and we hope to be able to report the top line response data at the end of 2020.

Our legacy drug, which we call ME-344 is a very interesting drug. This is a drug that interferes with the tumor cell’s ability to generate energy.

ME-344 inhibits mitochondrial function, so when we treat cells with our drug they cannot make energy through their mitochondria. In addition, when you treat tumors in animals and patients with anti-angiogenic therapeutics, which reduce the rate of glycolysis, the tumors oftentimes switch back to their mitochondria for energy. So we’ve just completed an initial study involving 40 women who were newly diagnosed with breast cancer. They received a course of therapy with the anti-angiogenic drug, Avastin, and then they were given either ME-344 or placebo.

We will compare whether the addition of our drug to Avastin has properties that were suggested by the animal studies; that is, the combination is a lot more potent in blocking cell growth of tumors compared with just Avastin alone.

Finally the most recent addition to our pipeline is a drug called Voruciclib, a small molecule inhibitor of CDKs (cyclin-dependent kinases). This small molecule inhibits a kinase enzyme that is very important in regulating the ability of a cell to live or die. All cells have the evolutionarily conserved mechanism to induce cell death, called apoptosis. Cancer cells have figured out a way to circumvent these death signals and that is critical, in many cases, for them to continue to grow.

Voruciclib inhibits CDK9, which is required for the expression of the myeloid leukemia cell differentiation protein (MCL1), an anti-apoptotic protein. When elevated, MCL1 may prevent cells from undergoing cell death. Voruciclib is currently in Phase 1 testing for safety.

WuXi: Looking at the entire drug development process, what are a few key areas or processes you would change or improve in order for companies to bring better drugs to patients?

Dan Gold: I feel the FDA has come a long way, especially in oncology and other critical areas of medicine where there truly is a need for new drugs.

There’s always this kind of push and pull between academic rigorousness, which is generally the bar that FDA follows, and the real life experience. I think the FDA has come a long way to work with companies to come up with innovative drug solutions, so they can get their drugs out on the market.

Eventually we are all held to the standard that first and foremost the drug must be safe and that is the critical role of the FDA, which should never change. The other is to make sure a drug has activity so you are not depriving an individual of a beneficial effect of some other drug. So you want to make sure the patient is knowledgeably taking a drug that has some potential benefit and is safe.

In the setting where patients have limited options, the FDA is starting to do more and more in developing innovative approaches to balancing safety and efficacy. I think the agency is cognizant that eventually the marketplace will dictate if a drug is useful or not, but as long as it does not harm patients and there is an indication it has a benefit, then they are really striving to get those drugs out on the market as best as possible.

WuXi: What will be the one or two most significant technological advances in drug development over the next year or two?

Dan Gold: I grew up in the time before the genome was sequenced and learned how to do DNA sequencing the old way, and after that PCR (polymerase chain reaction) was developed and it revolutionized how we do science.

And then the other advancement is the investment in technology for sequencing genes in tumors or other disease settings where you can really pinpoint the mutation and have a drug available for those genetic defects. That’s going to continue to be a huge breakthrough.

Unfortunately for cancers, specifically, they by nature are highly mutable because of the fact that cancer cells divide on a very rapid basis. Cell division is the driver of evolution and there are random mutations that occur in DNA that are a key part of evolution.

Mutations occur all the time in cancer cells. What we’re all learning is when we sequence these tumors and pinpoint the genetic defects and treat them, another one will pop up that may have already existed and now it’s allowed to grow out.

The ability to identify all these defects in real time and have drugs available so that you can continue to sequentially treat patients will enable us to treat a lot of cancers more like a chronic disease than the acute situation people currently face.