Research and development
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Peplin has three products in various stages of pre-clinical and clinical development. These are each based on different formulations of its lead compound PEP005 (ingenol mebutate).
PEP005 (ingenol mebutate) Gel
Peplin's lead product is a topical formulation for PEP005 (ingenol mebutate) which is a gel. We are developing PEP005 (ingenol mebutate) Gel for the treatment of two diseases. The first is actinic keratosis (AK) which is a pre-cancerous lesion often referred to as solar keratosis or sun spots and the second is basal cell carcinoma (BCC), which is the most common form of skin cancer. Standard approaches to the treatment of these diseases comprise cryotherapy, usually with liquid nitrogen, for AK or surgical excision for BCC. Emerging topical treatments are also used. PEP005 (ingenol mebutate) Gel is being developed as a rapidly acting and cosmetically attractive non-surgical treatment for AK and non-melanoma skin cancer (NMSC). Peplin has filed investigational new drug (IND) applications with the Food and Drug Administration (FDA) in the US.
PEP005 (ingenol mebutate) Gel for AK
We recently completed our PEP005-006 Phase IIb clinical trial of PEP005 (ingenol mebutate) Gel (0.05%) for AK as a field-directed therapy for non-facial AK lesions, including lesions on the scalp. Field-directed therapy refers to the application of PEP005 (ingenol mebutate) Gel (0.05%) for AK to a broad area of sun damaged skin that includes AK lesion. Preliminary results from the trial of 222 patients suggested that PEP005 Topical for AK presents a favorable safety profile and is well tolerated at all tested doses.
Preliminary results are results that have been confirmed by us, but have not yet been presented to the FDA in a final report. The trial involved a single application of either 0.025% or 0.05% of PEP005 (ingenol mebutate) Gel for AK each day, for two or three consecutive days. The most common side effects were local skin responses, such as redness, flaking or scaling and crusting. Local skin responses typically resolved in two to four weeks after cessation of treatment. The trial evaluated three efficacy measures based on various clearance rates. On the primary efficacy measure, partial AK clearance rate, 75% of the patients in the highest dose group cleared three quarters or more of their lesions 57 days post-treatment and 56% of patients in the lowest dose group cleared three quarters or more of their lesions 57 days post-treatment. The two secondary efficacy measures were complete AK clearance and baseline AK clearance rate. In the highest dose group the complete AK clearance rate and baseline AK clearance rate were 54% and 58%, respectively, and in the lowest dose group were 40% and 42%, respectively.
We also recently completed our PEP005-007 Phase IIa clinical trial of PEP005 (ingenol mebutate) Gel for AK as a field-directed therapy for treatment locations on the face. This trial of 86 patients examined concentrations from 0.0025% to 0.025% PEP005 (ingenol mebutate) Gel for AK for two and three consecutive day dosing regimens. We believe that the results from this trial suggest that each dose of PEP005 (ingenol mebutate) Gel for AK studied at and below the MTD presents a favorable safety profile and is well tolerated. Based on these results, we plan to conduct a Phase IIb clinical trial to further study a range of doses from 0.005% to 0.015% PEP005 (ingenol mebutate) Gel for AK, applied daily for two or three consecutive days for further development in the treatment of AK lesions on the face or scalp.
As compared with other treatment alternatives, we believe that PEP005 Topical for AK could offer a combination of attractive benefits to patients seeking treatment for AK, including:
- a short two-to-three day treatment regimen;
- localized, transient and well-tolerated side effects;
- a unique mode of action distinct from other AK;
- a convenient, patient-applied, take-home prescription medication; and
- the ability to treat visible lesions and the surrounding sun-damaged skin where lesions may develop in the future.
AK is predominantly treated using either cryotherapy alone, cryotherapy in conjunction with topical agents or topical agents alone. We believe the shortcomings of current topical treatments have limited their broader adoption. We believe PEP005 (ingenol mebutate) Gel for AK could address these shortcomings and has the potential to expand the markets for both topical agents used in conjunction with cryotherapy, and topical agents used alone, to treat AK. Cryotherapy is a quick and well established treatment alternative in which the clinician removes clinically-obvious AK lesions by applying a cryogen, or extreme cold, for a sufficient period of time to destroy the lesion.
Prior to filing a new drug application, or NDA, for PEP005 (ingenol mebutate) Gel for AK for the treatment of AK lesions, we will need to complete a series of clinical trials in two general anatomical areas, on-head, which comprises areas on the face or scalp, and off-head, which primarily comprises areas on the back of the hand, arm, shoulder and back. We expect this program will require at least two pivotal Phase III clinical trials comprising one Phase III clinical trial for off-head applications and one Phase III clinical trial for on-head applications, in each case together with supportive safety and other studies.
PEP005 (ingenol mebutate) Gel (0.05%) for AK (non-Head)
After completing our PEP005-006 Phase IIb clinical trial, we submitted the results of the trial to the FDA and, upon review, the FDA stated that the trial was an adequate dose ranging trial for applications of PEP005 (ingenol mebutate) Gel for AK to AK lesions in non-facial treatment locations. We received a Special Protocol Assessment (SPA) from the FDA in May 2008 confirming the design, clinical endpoints and planned statistical analyses of Peplin's Phase III trial protocol are adequate to form the basis for approval of a new drug application (NDA) for off-head applications. As a result of the SPA agreement, we plan to initiate our Phase III clinical trial in the third calendar quarter of 2008.
PEP005 (ingenol mebutate) Gel (0.005%-0.015%) for AK (Head)
We expect to initiate a Phase IIb dose ranging trial for on-head applications during the second calendar quarter of 2008. This Phase IIb clinical trial is intended to support the design of our subsequent Phase III clinical trial for on-head applications, which we plan to initiate in 2009.
We expect to file a single NDA for applications on both on-head and off-head treatment locations with the FDA mid-2010, assuming our successful end-of-Phase II meeting with the FDA and the successful completion of our Phase III clinical program.
PEP005 (ingenol mebutate) Gel for BCC
The preliminary results from our most recent PEP005-003 Phase IIa clinical trial of PEP005 (ingenol mebutate) Gel for BCC, suggest that this drug candidate presents a favorable safety profile and is well tolerated. Further, a statistically significant portion of superficial BCC tumors in the 60 patients studied were cleared with just two applications of 0.05% PEP005 (ingenol mebutate) Gel for BCC. We intend to develop PEP005 (ingenol mebutate) Gel for BCC as an in-office, physician-applied treatment procedure for superficial BCC tumors. We are presently conducting a Phase II trial of PEP005-009, a dose escalation clinical trial in which we are increasing the dosage of PEP005 (ingenol mebutate) Gel for BCC to establish the MTDs when administered as a single application and when administered as two applications one week apart. We are also evaluating the tumor clearance rate at the MTDs. We must successfully complete these and other trials before we can seek regulatory approval to commercialize this product candidate. We do not expect to commence or Phase III clinical program for PEP005-009 until 2010.
The vast majority of BCC tumors are treated by surgical methods. However, we believe that the associated pain and morbidity, together with the potential for long term surgical scars that accompany surgery represent an important shortcoming of this treatment approach. Further, we believe that physicians and their patients would embrace an effective and well-tolerated topical alternative to surgery. We believe PEP005 (ingenol mebutate) Gel for BCC has the potential to be a prominent treatment option for smaller and well demarcated superficial BCC tumors.
To view an animation of Peplin's development of its anti-skin cancer drug, click here.
PEP005 (ingenol mebutate) for injection for leukemia
PEP005 (ingenol mebutate) for injection is an intravenous formulation of PEP005 (ingenol mebutate) which Peplin is developing to treat leukemia, a cancer that starts in blood-forming tissue such as bone marrow, causing cancer cells to be produced and enter the blood stream.
Peplin has conducted a number of studies to evaluate the potential of PEP005 (ingenol mebutate) as a systemic therapy for leukemia. The results of research into the anti-leukemia properties of PEP005 (ingenol mebutate) were published in Blood, the journal of the American Society of Hematology, providing international recognition of the potential of PEP005 as a new therapy against leukemia. This research showed that PEP005 (ingenol mebutate) has potent anti-leukemia properties and that healthy cells are unaffected by the same concentration of PEP005 (ingenol mebutate), indicating the potential for a broad therapeutic window. It also demonstrated an additive effect of PEP005 (ingenol mebutate) when used in combination with ATRA (an approved use anti-leukemia drug), indicating the potential for combination therapy. The paper also postulates a mechanism of action via the activation of the delta isoform of protein kinase C. This is an important discovery and may provide a biomarker for a simple test to identify patients who could benefit from this therapy.
Peplin has completed a pre-IND meeting with the FDA and has a clear view on the pre-clinical package required to file an IND and the initial clinical plan for the drug's development. Much of the pre-clinical development has been completed; certain additional toxicology studies remain outstanding for the IND.
To view an animation of Peplin's anti-leukemia drug, click here.
PEP005 (ingenol mebutate) for intra-cavitary delivery for bladder cancer
The potential for the use of PEP005 (ingenol mebutate) in a localized format (such as topical, intra-lesional or other site specific formulation) is based on extensive mouse model work where this form of therapy has successfully cured a wide range of mouse and human tumors. Peplin is focused on the potential of PEP005 (ingenol mebutate) as a local therapy in the form of an intra-cavitary wash as an adjunct to surgery for superficial bladder cancer. Approximately 75% of bladder cancer presents as superficial, with the balance as invasive. Superficial bladder cancer is currently most often treated with a transurethral resection which is often followed by a local intra-cavitary chemotherapy as a wash. Recurrence rates following transurethral resection are reported to be around 50% after 12 months. The fact that current approaches are both only modestly effective and accommodate a local chemotherapy aspect supports the potential for PEP005 (ingenol mebutate) in this area.
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