All About Pepaxto (Melphalan Flufenamide)

All about PEPAXTO or Melphalan Flufenamide. Since the filming of this video, OncoPeptides made a decision to voluntarily withdraw the U.S. accelerated approval of PEPAXTO. This difficult decision was made following consultation with the FDA regarding the results of the Phase III Ocean Study. Melphalan Flufenamide goes by several different names. The formal scientific name is Melphalan Flufenamide. You also may have heard it referred to as Melphalufin. You may also hear of it as PEPAXTO. Melphalan Flufenamide, as you can perhaps understand from the name, actually belongs to a class of chemotherapeutic agents called alkylators. There are other alkylators that we also use in multiple myeloma, and that would include Melphalan, which is commonly used in high doses as part of a tologist stem cell transplant as consolidation therapy for myeloma. We also use cyclophosphamide frequently in a number of different myeloma therapies. Cyclophosphamide is an alkylating agent as well. And in some cases, the alkylator Ben-Demostene will sometimes be used in combination therapies for patients with relapsed refractory multiple myeloma. So Melphalan Flufenamide is a novel spin on an old idea, that old idea being alkylator therapy for multiple myeloma. So Melphalan Flufenamide is a peptide drug conjugate. And what that means is that the alkylator portion of the therapy is attached to a peptide. This peptide is what we call lipophilic. What that means is it's fat loving. That allows it to actually cross the cell membrane, the surface of the myeloma cell inside quite readily. Inside myeloma cells, as well as other cancer cells, there are a class of enzymes called amino peptidases that are responsible for basically functioning as scissors and clipping peptides into smaller pieces. These amino peptidases will actually clip or scissor off that peptide off of the Melphalan and liberate a hydrophilic Melphalan in the cell. So it's trapped inside the myeloma cell. Hydrophilic means water loving and it's therefore trapped inside the myeloma cell. Now there are amino peptidases in normal tissues of the body, but there is a higher proportion of amino peptidases in cancer tissues, including in multiple myeloma. So the idea here is that you're targeting, at least in a relative way, the alkylator, the Melphalan payload to the myeloma by virtue of the fact that there are more amino peptidases inside those myeloma cells that can clip off that peptide and liberate and trap the active alkylating agent inside the myeloma cell. Where it then goes into the nucleus, mediates DNA damage in the cancer cell and causes it to die. Melphalan does not have that. It's not a peptide drug conjugate. It's not lipophilic. It does not readily traverse the myeloma cell surface inside. So you can get a higher concentration of alkylator with Melphalan flufenamide by virtue of its lipophilicity or fat loving nature, if you will, and the amino peptidase mediated activation inside the myeloma cell. And there's actually pretty nice preclinical data from the Dana-Farber Cancer Institute that shows just that, that the concentrations of alkylator that you get in myeloma cells with Melphalan flufenamide is actually quite higher than what you see with just regular old Melphalan. And by virtue of that, the concentration of drug that's required to achieve the same effect with Melphalan flufenamide relative to Melphalan is 50-fold less. What are common side effects of PEPAXTO? So as far as the side effect profile, the relative targeting by virtue of higher peptidase or amino peptidase levels in myeloma cells, so we think that does play a role in its more favorable side effect profile. You know, I do want to urge a little bit of caution here. I mean, there's clearly amino peptidases present in bone marrow precursor cells because one of the most common side effects of Melphalan flufenamide is low blood counts. So low white blood cell count and in particular low neutrophil count actually is quite common with Melphalan flufenamide, and it can actually be quite severe. And that's something that needs to be monitored very carefully for any patient that's on this therapy. Similarly, low platelets is also a common side effect, and the drop in platelet count can actually be quite severe as well. So patients, again, need to be monitored very closely, have their counts checked regularly just to ensure that they don't need any additional support in that regard. So it is a relative targeting. But aside from the low blood count issues with the drug, the side effect profile is quite favorable. Yes, we see fatigue. Yes, we see nausea. Yes, we see diarrhea. Certainly not nearly as common as the issues with low blood counts. And thankfully, those non-hematologic side effects are clearly less severe. And that may in part be due to the fact that it's a more targeted therapy. As far as the issue with hair loss, it is absolutely true that Melphalan flufenamide does not lead to hair loss. But, you know, when Melphalan is given at lower doses, it also does not. It's only when it's given at higher doses that Melphalan actually causes hair loss, like in the setting of a stem cell transplant, for example. Other reported side effects include changes in kidney function, blood tests, fever, and respiratory tract infections. These are not all the possible side effects of PEPAXTO. You were encouraged to report any side effects you were experiencing to your health care provider. How are these side effects managed? So as far as managing the side effects of Melphalan flufenamide with regards to the hematologic side effects, or specifically the low white blood cell count and low neutrophils, you know, I would say that the majority of patients will require growth factor support for their neutrophils, whether that's in the form of neupogen or neulasta or some equivalent of one of those agents. Those are therapies that are commonly used to shorten the duration of time that the neutrophil count is low. And by so doing, reduce the risk of infection with regards to low platelets. You know, the primary way of managing that is by monitoring of the counts and transfusing platelets, you know, when necessary. There are growth factors or what we call tipomimetics, such as N-plait or romeplostom, that we sometimes use to support platelet counts in patients on chemotherapy. That is not an on-label indication for that type of treatment, but sometimes we can use that successfully. And then the low red blood cell counts or anemia is managed with red blood cell transfusion and sometimes with growth factor support. So for management of non-hematologic side effects of Melphalan flufenamide, we will give an anti-nausea medication as part of the pre-medications for administration. It is given intravenously, and actually, at least for now, it's given through a central venous catheter, say, for example, through a port, and it's done once every four weeks. So we will give an anti-nausea medication before we administer the IV Melphalan flufenamide. And we do provide patients with an anti-nausea medication that they can take on an as-needed basis when they're at home. So the FDA approved administration of Melphalan and flufenamide is as an intravenous infusion, which is given on a once every four week basis. For now, Melphalan flufenamide needs to be given through a central venous catheter. That could be through a port, for example. A patient may have a PICC line as another example. And again, it's given on a once every four week basis. It is given with a weekly dose of dexamethasone. I know that there are many patients out there that would love to completely get rid of dexamethasone in a number of our different regimens. With regards to Melphalan flufenamide, in the initial phase one to study of Melphalan flufenamide with dexamethasone, there was a small cohort of patients that they treated with just Melphalan flufenamide alone. And the response rates were not as high. In addition to that, the dexamethasone probably helps a little bit with that initial nausea that could potentially occur with administration of the Melphalan flufenamide on that first day. So for that reason, just given the higher response rates and perhaps some anti-nausea properties of the steroid, the Melphalan flufenamide is given with weekly dexamethasone. So Melphalan flufenamide is given as a flat 40-milligram dose, and the IV infusion is over 30 minutes. What is the indication of PIPAXTO? So the FDA indication or label, if you will, for the accelerated approval of Melphalan flufenamide with dexamethasone are patients who have relapsed multiple myeloma, and importantly they have to have received four prior lines of therapy for their multiple myeloma. So these are patients who have seen all of the usual myeloma therapy suspects. They've seen the proteasome inhibitors such as vortezomib, carfilzomib, and exazomib. They've seen the immunomodulatory drugs such as lenalidomide and pomalidomide. You know, they've seen the CD38 antibodies such as daratumumab and esotuximab, and the overwhelming majority of these patients have disease that has become resistant to all three of these drug classes. What else is important for a patient to know about PIPAXTO? The ideal patient for the combination of Melphalan flufenamide and dexamethasone is somebody who has had at least four prior lines of therapy. I think patients who have what we call triple class refractory disease, in other words, myeloma that has become resistant to at least one of the proteasome inhibitors, one of the immunomodulatory drugs, and one of the CD38 antibodies, a patient who has good blood counts, a neutrophil count at baseline of at least a thousand or better, ideally 1,500 or better, a platelet count of at least a hundred or higher, and a patient who does not have alkylator resistant disease. In other words, someone who's not already resistant to, say, Melphalan or cyclophosphamide or bendimustine. That is the ideal patient. And it is important to recognize that at least in this day and age with myeloma therapy, the majority of patients who would be considered for this agent do not in fact have alkylator resistant disease. A lot of patients will have only received an alkylating agent treatment in the context of autologous stem cell transplant, and that's it. So it may have been many years since their myeloma was even exposed to that class of drugs. I think the key point is that the patients that are good candidates for this therapy are those that have very good bone marrow reserves, because again, you know, the more severe side effects with this drug are low blood count issues, low neutrophils, low platelets, and anemia, and that's what needs to be monitored very closely. Will I need a port? For a patient who's considering melphalan, flufenamide, and dexamethasone and does not already have a central venous catheter, you know, we typically advocate that they have a port placed for administration. I think it's a better long-term solution for administration of therapy than a PICC line, for example. And, you know, a port can be very useful for patients with subsequent therapies. A lot of our patients who are on carfilzomib-based therapy, for example, just given the frequency of IV infusions that are required with carfilzomib, you know, a lot of our patients will actually already have ports in to begin with. And then the other nice thing about the port, obviously, is you can have labs drawn through them. Why is a port needed? So the concern about, you know, peripheral IV administration of melphalan, flufenamide is the concern for phlebitis, or irritation of the smaller caliber veins, you know, that are in the arms, for example. Whether that's really the case or not I think remains to be seen. There's actually a small study that Oncopeptides is actually running as we speak, which is looking at the safety and the feasibility of administering melphalan, flufenamide through a peripheral IV. And we'll have to wait for those results to mature to see whether or not we can safely do it through peripheral. But for now, a central venous catheter is the way to go, and I think a port is the best way to achieve that. Throughout your treatment journey, the OnCourse patient support program helps you and your care partner navigate the way with valuable support resources. When you enroll, a dedicated OnCourse nurse will be your point of contact to support you with the program. OnCourse provides assistance for you and your caregiver when evaluating your prescription insurance coverage options. OnCourse offers financial resources that are available to help you pay for your medication. Your dedicated nurse will let you know what to expect and answer any questions you have about the OnCourse program. You will be given a direct line of communication to your nurse whenever you need them. Be sure to consult with your doctor first for medical advice or if you experience any side effects while on treatment.