PhotoCure Basal Cell Carcinoma Phototherapy Has “Niche” Market Potential

PhotoCure's methyl aminolevulinate could be approved as part of a "niche" basal cell carcinoma phototherapy regimen for patients who are intolerant to other treatments, an FDA advisory committee said in voting against a broader indication.

"I think this is a niche product. I think this potentially has a role for a subset of patients that we need something for," FDA Dermatologic & Ophthalmic Advisory Committee consultant Lynn Drake, MD, Massachusetts General Hospital, said at a Sept. 10 meeting.

The committee voted 10-2 that the benefit-risk profile of the methyl aminolevulinate regimen is insufficient to support approval of the broader indication sought by the company. [To ¹ order a video of this committee meeting, visit FDAAdvisoryCommittee.com.]

Basal cell carcinoma patients who could potentially benefit from the methyl aminolevulinate regimen include those with large superficial lesions on the lower legs, diabetics and patients on anticoagulants, Drake said.

"I think these are problem patients. I also think there's some patients that just due to a variety of reasons really don't want cold steel surgery, and if you have something less invasive or problematic, oftentimes they might be very grateful for that opportunity."

PhotoCure's photodynamic therapy regimen is a three-hour application of 168 mg/g methyl aminolevulinate cream followed by red light exposure from a CureLight Broadband lamp (MAL-PDT). PhotoCure markets MAL as Metvix overseas but is considering other trade names to avoid potential medication errors with Penederm's antifungal Mentax (butenafine).

FDA asked the committee to consider methyl aminolevulinate phototherapy in the context of available basal cell carcinoma treatments and, if approved, how the patient population should be identified in product labeling.

Committee members should consider "what is already out there for basal cell carcinoma and how this product may fit into the overall armamentarium," as well as the "potential tools we have in labeling" to help define an indication, FDA Dermatologic & Dental Drug Products Division Director Jonathan Wilkin, MD, said.

Committee consultant Lloyd King, MD/PhD, Vanderbilt University, agreed "there are a lot of patients...who need a niche product," but cautioned that "we should be very careful about how we define the issues here: niche versus broad-based."

"I certainly don't think that there ought to be broad claims or broad indications," Drake said. "I think it's a niche drug, and I've seen this committee approve niche products before."

FDA's Wilkin appeared amenable to the idea. "I think what we heard today is looking for a niche - which I think is fair. I mean, looking at the overall data set and trying to make the assessment" of whether there is "another way of looking at that."

However, the committee recommended against a broader indication, voting 9-3 that the data do not support first-line use.

PhotoCure's proposed indication is for the treatment of nodular and superficial basal cell carcinoma where surgery is not desired. The indication would not include high-risk patients, the company noted.

If approved, MAL-PDT would be positioned as a regimen that delivers a better cosmetic result than other available modalities and one that can be used multiple times while preserving the option to switch to other therapies, PhotoCure told the committee.

"There are a number of patients who...don't want scars on the face," the firm said at the meeting. "You can use this treatment practically an unlimited number of times" and still "keep open all other options, and if you heal them...without any scars, the patients are very happy."

Committee member Robert Katz, MD, (Rockville, Md.) disputed the appropriateness of such positioning. "We should not spend too much attention on the cosmetic issue, because obviously if you have a treatment that gives a much poorer result, you're going to get better cosmetic results...because you're not getting rid of all those other tumors."

In questioning the adequacy of the efficacy results, the committee cited a low number of enrolled patients and wide confidence intervals. PhotoCure conducted two six-month placebo-controlled studies in 131 patients, and two 48-month, open-label, non-inferiority studies designed to look at recurrence rates.

In the placebo trials, patients received two treatment cycles seven days apart and were followed for three months. Patients with a partial response received a second round of treatment. Those with a complete response were followed for five years, while patients with no response had their lesions surgically excised.

In an FDA analysis of the data, 73% of MAL-PDT patients in study 307 had a complete response (CI: 54%, 87%), versus 25% of placebo patients (CI: 11%, 43%). In study 308, 64% of MAL-PDT patients had a complete response (CI: 45%, 80%), versus 15% on placebo (CI: 5%, 32%).

FDA also presented an analysis of the first treatment cycle, which showed a 56% response rate for MAL-PDT, compared to a 23% placebo response based on a histological evaluation. Using both a clinical and histological evaluation, the first-cycle response rate dropped to 46%, the agency said.

Katz argued that the response rates are "insufficient" given other available treatments and the lengthy process involved in administering MAL-PDT.

"We're talking about a treatment that is better than placebo, but in practice if you offered to a patient a treatment that was better than placebo and they had to go through all of this: wait for three hours, have two treatments, come back in three months for another trial with two treatments....It's very insufficient."

Katz later agreed that "if the sponsors could show...a niche, where we could say, 'oh yes, that's a place that we could use in that patient as advantageous over what we had available,' it would be very interesting."

PhotoCure conducted two open-label, non-inferiority trials against surgical incision (study 303) and cryotherapy, or liquid nitrogen spray (study 304).

MAL-PDT demonstrated non-inferiority to the other procedures in both studies at six months, but PhotoCure noted that MAL-PDT led to more treatment failures than surgery over time. At two years, MAL-PDT treatment failure was 15% versus 3% for surgery.

The committee expressed concern with recurrence rates among MAL-PDT patients in study 303. Two-year lesion recurrence rates ranged between 9% and 34% for MAL-PDT. By comparison, surgical excision recurrence rates ranged from 2% to 16%.

FDA guest speaker and surgical dermatologist Steven Rotter, MD, presented five-year recurrence rates for other basal cell carcinoma therapies: surgical excision (2.8%); curettage and electrodessication (4.7%); radiation (5.3%); cryotherapy (3.7%); and Mohs micrographic surgery (1.4%).

Committee members also expressed concern with how the lesions were prepared prior to methyl aminolevulinate application, noting that debulking differences could explain high placebo response rates and variability between certain study centers.

Investigators were instructed to curette the lesion prior to MAL therapy to allow for penetration of the active drug ingredient. Committee members questioned whether some investigators engaged in therapeutic curettage (completely removing the lesion), which could account for the 25%-30% placebo response rates.

FDA also asked the committee to consider a high potential for sensitization to MAL-PDT, which was at least 52% in one safety study in healthy patients. In addition, two cancer patients in clinical trials reported a urticaria/hypersensitivity reaction, and two patients in European postmarketing experience were sensitized to MAL-PDT, with one positive rechallenge.

Committee consultant Eileen Ringel, MD, (Waterville, Maine) suggested PhotoCure conduct longer-term studies to evaluate sensitization rates over multiple treatments and recommended repeated three-hour patch applications until sensitization is achieved.

Adverse events were common, with 81% of patients reporting an event (75% local and 27% non-local). Most non-local AEs were not systemic and were either lesions at another site or surgical intervention for a pre-existing lesion.

Phototoxicity was a common local AE, with pain, burning or stinging skin, edema and erythema localized to the treatment area. Most local events were mild (53%), with 37% moderate and 10% severe.

Oslo, Norway-based PhotoCure filed the NDA (21-576) for basal cell carcinoma Feb. 21, followed by a 120-patient safety update on July 16. An NDA for actinic keratosis filed in September 2001 has been deemed "approvable" by the agency; PhotoCure submitted a response in July.