Oncopeptides AB (Nasdaq Stockholm: ONCO), a Swedish pharmaceutical company headquartered in Stockholm that develops targeted therapies for blood-based cancers, has announced the final results of the pivotal phase 2 HORIZON (OP-106) clinical study, which evaluated the efficacy and safety of Oncopeptide’s first-in-class peptide-drug conjugate melflufen for the treatment of triple-class refractory relapsed refractory multiple myeloma (RRMM).
Melflufen (INN melphalan flufenamide) is a multiple myeloma treatment engineered to have a chemical structure that promotes its concentration in multiple myeloma cells and delivery of a destructive payload of alkylating agents. The drug has shown cell-killing activity against tumor cell lines resistant to other cancer therapies.
- Melflufen Phase 2 HORIZON Clinical Trial Results
- Multiple Myeloma Treatment and Prognosis
- Cutting Edge Multiple Myeloma Treatments
- Melflufen Mechanism of Action: Alkylating Agent Melphalan
- Melflufen Phase 1/2 Clinical Trial Results
Melflufen Phase 2 HORIZON Clinical Trial Results
CEO of Oncopeptides AB Jakob Lindberg stated, “The presentation of final data from our pivotal HORIZON study, with competitive results in triple-class refractory myeloma patients, represents the most important milestone for Oncopeptides to date. These data confirm that melflufen has a good efficacy and safety profile in triple-class refractory myeloma patients – a fast-growing patient population with significant unmet medical need and lack of approved treatments. The safety profile was consistent with previous melflufen studies with good tolerability and a low rate of non-haematological adverse events.”
Dr. Lindberg continued, “We firmly believe that melflufen has the potential to become an important treatment option for patients with relapsed refractory multiple myeloma. Study physicians and clinical sites have been immensely supportive and with their help we are on schedule to submit the NDA for accelerated approval end of Q2 2020.”
Multiple Myeloma Treatment and Prognosis
According to the American Cancer Society, multiple myeloma is a cancer of plasma cells, a specialized subset of white blood cells found primarily in the bone marrow. Plasma cells are derived from B cells and produce antibodies as part of the immune response to infection and other events.
In multiple myeloma, the activity and proliferation of plasma cells becomes uncontrolled, leading to kidney problems, decreased functionality of the immune system against infections, bone pain and fractures, and low counts of platelets, red blood cells, and normal white blood cells. In 2015, multiple myeloma affected 488,000 people around the globe and led to 101,100 deaths with a five-year survival rate of approximately 49%.
The HORIZON study involved 157 patients with difficult-to-treat multiple myeloma that failed therapy with proteosome inhibitors, immunomodulatory agents, and anti-cancer monoclonal antibodies, the standard-of-care “triple-class” therapies for patients with newly diagnosed or recurrent multiple myeloma.
Patients with multiple myeloma resistant to these three treatment options, which comprise the typical myeloma treatment protocol, are regarded as having triple-class refractory disease and have poor survival outcomes and limited cancer treatment options. The development of improved therapies for this subset of multiple myeloma patients is an important clinical and research goal.
Among the patients in the clinical trial cohort, some had high-risk multiple myeloma with cytogenetic features predictive of a poor prognosis and some had tumor metastases that spread from the bone marrow to other soft tissues or organs in the body, known as extramedullary disease (EMD).
The patients in the HORIZON study were refractory to pomalidomide and/or daratumumab, currently approved therapies for RRMM, and received subsequent drug therapy with melflufen.
Cutting Edge Multiple Myeloma Treatments
Currently, triple-class refractory multiple myeloma is treated with salvage autologous stem cell transplantation, conventional chemotherapy, radiation therapy, and the attempted re-use of triple-class therapies, which generally provide only temporary relief from cancer progression and are not curative.
Treatments for triple-class refractory disease currently in development include chimeric antigen receptor (CAR) T-cell-based therapies, next-generation monoclonal antibodies, inhibitor of nuclear export selinexor, small-molecule B-cell lymphoma (BCL)-2 inhibitor venetoclax, and bi-specific T-cell engagers, which physically link T-cells to cancer cells to promote anti-cancer immunity.
In addition, treatments that complement existing immunotherapies are also being developed, such as light-activatable nanoparticles that enhance checkpoint inhibitor blockade therapy for solid tumors.
There is currently no completely curative multiple myeloma treatment. It is likely that the treatment plan for multiple myeloma will continue to evolve as new therapies are introduced into the clinic. A new drug for multiple myeloma could be clinically available in the not-distant future.
Melflufen Mechanism of Action: Alkylating Agent Melphalan
Alkylating agents, which chemically alter DNA, exploit the increased sensitivity of rapidly-dividing cancerous cells to DNA damage as compared to healthy cells. Melflufen is a targeted peptide-drug conjugate whose mechanism of action involves the rapid delivery of a payload into tumor cells of the alkylating chemotherapy agent melphalan.
After entering myeloma cells, the chemical structure of melflufen enables cleavage of the molecule by intracellular enzymes known as peptidases and yields melphalan which is intended to have anti-cancer activity.
In preclinical studies, melflufen has shown efficacy for the inhibition of blood vessel growth to tumors, which is important for supporting tumor growth and eventually metastasis of cancerous cells to other sites within the body, and for the inhibition of the induction of DNA repair by tumor cells, a process that enables tumor cells to survive DNA damage and continue proliferating. By chemically linking strands of DNA, melphalan prevents the synthesis of DNA and RNA, which are necessary for cell survival.
Melflufen has shown cytotoxic activity against cell lines of multiple myeloma resistant to other cancer therapies including alkylating agents. According to the press release, “The final HORIZON data reinforce Oncopeptides’ view that melflufen could play an important role in the treatment of patients with RRMM.” Overall, the response rate of triple-class RRMM patients to melflufen in the HORIZON study was found to be 26%.
A phase 3 clinical trial of melflufen, known as the OCEAN (OP-103) study, is currently enrolling and will directly compare melflufen to standard-of-care therapies for the treatment of RRMM. These clinical trials are important for identifying and evaluating potential symptoms and side effects associated with the use of candidate multiple myeloma treatments and are intended to verify their safety and efficacy prior to their approval for broader use in the clinic.
Melflufen Phase 1/2 Clinical Trial Results
On March 24th, 2020, Oncopeptides AB announced the publication of results from its phase 1/2 study (O-12-M1) evaluating the efficacy of melflufen plus the corticosteroid dexamethasone for the treatment of RRMM. RRMM patients that had failed prior treatment (lines of therapy: median 4, range 2-14) received a weekly dose of dexamethasone and 40 mg of intravenous melflufen once every four weeks.
Patients receiving both drugs according to this dosing schedule had a 31% overall response rate, 8.4 month median duration of response, 20.7 month median overall survival, and 5.7 month median progression-free survival.
The overall survival indicates how long cancer patients receiving the drug combination survived relative to those that received a control, and is a measure of clinical benefit of the drug combination for prolonging life. The duration of response refers to the length of time between the achievement of an anti-cancer response and disease progression.
Progression-free survival, which assesses the ability of a therapy to stabilize developing disease, indicates how long a patient lives without cancer growth or metastasis. The overall response rate refers to the proportion of patients that experienced a measurable decrease in the size of their tumor after receiving multiple myeloma therapy.
Chief Medical Officer of Oncopeptides AB Klaas Bakker, MD, PhD, stated, “We are excited to share with the scientific community these findings from our phase 1/2 study of our peptide-drug conjugate, melflufen. The results published today served as the foundation of our broad clinical development program.”
Dr. Bakker continued, “We recognize the significant unmet needs of patients with RRMM who currently have few available treatment options and are in desperate need of well-tolerated treatments with the potential to overcome cancer resistance patterns. I would like to thank all patients and their care partners for participation in this study.”