[Beacon Staff]

FDA declines to approve new IV melphalan formulation

by Beacon Staff on Fri Oct 23, 2015 12:52 pm

Many people here may recall that there has been a "new and improved" formulation of IV melphalan under development. It's been described as ""Captisol-enabled melphalan", and the formulation has been under review this year for potential approval by the U.S. Food and Drug Administration (FDA).

The company developing the new formulation had asked the FDA to approve the drug so that it could be used as a substitute for standard IV melphalan during the high-dose chemo part of the autologous stem cell transplant process for multiple myeloma patients.

Well, the FDA has decided that it's not ready at this time to approve the new formulation, which goes by the brand name "Evomela." Spectrum Pharmaceuticals, the company that is de­vel­oping Evomela, issued a press release about the FDA decision early this morning. Here are a few excerpts from the release:

Spectrum Pharmaceuticals ... today that it has received a Complete Response Letter from the U.S. Food and Drug Administration (FDA). A Complete Response Letter is a com­muni­ca­tion from the FDA that informs companies that an application cannot be approved in its present form. In the letter, the FDA did not identify any clinical deficiency in Spectrum’s [New Drug Application] package.

“We will work swiftly with the FDA to address the Complete Response Letter,” said Rajesh C. Shrotriya, MD, Chairman and Chief Executive Officer of Spectrum Phar­ma­ceuticals. “We remain com­mitted to bringing EVOMELA to the market for patients and plan to work closely with the FDA.”

Evomela is a new, propylene glycol-free melphalan formulation that demonstrated bio­equivalence to the standard melphalan formulation (Alkeran) in a Phase 2 clinical study (Aljitawi et al, Bone Marrow Transplant, 2014). Evomela has been granted Orphan Drug Designation by the FDA for its use as a high-dose con­di­tion­ing regimen for patients with multiple myeloma undergoing ASCT.

Evomela's formulation eliminates the need to use a propylene glycol containing cus­tom diluent, which is required with other intravenous melphalan formulations, and has been reported to cause renal and cardiac side effects. The use of the Captisol® technology to reformulate melphalan also improved its stability, extending its use time to five hours, which is anticipated to simplify preparation and ad­min­istra­tion logistics, and allow for slower infusion rates and longer administration durations for pre-transplant chemotherapy ...

Captisol is a patent-protected, chemically modified cyclodextrin with a structure designed to optimize the solubility and stability of drugs. ... This unique technology has enabled six FDA-approved products, including Amgen’s Kyprolis ..."

You can view the full text of today's Spectrum press release here:

"Spectrum Pharmaceuticals Receives Complete Response Letter (CRL) From U.S. Food And Drug Administration (FDA) For EVOMELA™ (Melphalan) For Injection" (Oct 23, 2015)

[JPC]

Re: FDA declines to approve new IV melphalan formulation

by JPC on Sat Oct 24, 2015 5:49 am

I was not aware of this drug and issue, but then again, after reading the article, I recall that this was discussed by one of the "expert" panels briefly that I had viewed a couple of months ago. One doctor pointed out that this is something that primarily is a benefit to the pharmacist, the nurses, and the technicians. Patients (and doctors for that matter) do not understand the difficulty in "cooking" (or mixing) the melphalan, it is difficult, has temperature issues, it deteriorates rapidly, etc. I believe it has to be administered almost immediately after mixing, and has very narrow ranges of temperature that it can be stored in that time (an hour or two?). Another doctor stated, yes the primary benefit is for the support staff, but streamlining that process for the supports staff is still a good thing, and would enhance their ability to care for the patients.

I also recall being advised that a portion of the side effects from the ASCT were in the preservatives, primarily in the stem cells, but also in the melphalan. That could be a relatively small benefit in and of itself, but I am guessing that the lion's share of the side effects come from the melphalan itself (and the killing off of the while blood cells) I don't think that denying this is a major issue for the patients, its just curious that since this has been used in 6 other drugs already, and seems to be safe, what caused them to deny the app?

[Christa's Mom]

Re: FDA declines to approve new IV melphalan formulation

by Christa's Mom on Sat Oct 24, 2015 8:42 am

I would guess increased cost with very little benefit for the patient.

Lyn

[cindylouise]

Re: FDA declines to approve new IV melphalan formulation

by cindylouise on Sat Oct 24, 2015 10:09 am

I'm trying to see if I understand what you are saying JPC. So the new formulation allows them more time from prep to use. Which is good. But it also states fewer kidney and cardiac side effects. I'm not understanding how this wouldn't be a big deal for patients? Reduced ejection fraction (EF) disqualified my husband for transplant. I have no idea if the melphalan was the reasoning for this, but still think any drug that reduces organ damage has a great potential for many patients.

[JPC]

Re: FDA declines to approve new IV melphalan formulation

by JPC on Sat Oct 24, 2015 11:15 pm

Hello Cindylouise:

Actually, in our case, we do have a little bit of experience with reduced ejection fraction issue. For my wife it came up bad on the EKG, so they did a heart MRI (yes, one more unplanned test when we were prepping for the ASCT), which was a more accurate test. The EF came in at 90%, which is borderline normal (contradicting the EKG). If it's less than 90%, they do a cardiac consult. I am not asking for you to post your husband's actual EF, but I will tell you that I asked at what point would you entirely rule it out. The answer was that it's on a case-by-case basis, but ASCTs might be done on patients with EF's in the 50-60 range, based on other factors. My point being that if it's in the 70's or 80's, there are other centers that would do the ASCT. If its lower than that, not likely.

In my earlier post, I was more asking a question than making a statement, but I do agree with your point. Sometimes improvements are small baby steps, and not quantum leaps. Over time, a lot of baby steps do add up. Good luck to you and your husband.

[JPC]

Re: FDA declines to approve new IV melphalan formulation

by JPC on Sun Oct 25, 2015 9:08 am

Hi Lyn:

Thanks for answering my question, and you may well be correct or at least close to the reason.

In retrospect, on reading your comment and Cindy's comment, I am able to put my point a bit more clearly in words. Should not the FDA give a clear answer back on all applications? Obviously, the drug company would like to know that, and so would a larger community interested in multiple myeloma research. The "no explanation" part rubbed me the wrong way. I have filled out government forms in my work, and I am sure it takes several people and several days just to fill out the forms. To get no explanation at all is not good.

Relatedly, I have read several of the pamphlets on general literature on clinical trials, I believe they come from the NIH. I have not taken a deep dive into the details of the drug application. The process, I understand, is not supposed to consider cost / economics. It is supposed to consider safety and efficacy. The 3 criteria that I have read are:

1) Clear, documented improved outcomes;
2) Similar outcomes with lower side effects; and
3) Unmet treatment needs.

In this case, the first criteria would be out, the second criteria would be in play, so they would need to evaluate whether it was enough of a benefit. Some commentary on that point I think would have been appropriate.

Regards