Endometrial cancer is the most common cancer of the female reproductive system. Advanced cases have virtually no effective treatments. Surgery, alone or in combination with radiation, chemotherapy, and/or hormonal therapy are good as initial therapy. In advanced stages, however, surgery has no role to play and chemotherapy has limited, if any, benefit.
That’s why when Merck and Ariad (ARIA) learned about the promising results of interim phase 2 study of Ariad’s mTOR inhibitor ridaforolimus, they stopped further enrollment to follow patients’ survivability. Indeed, the results demonstrate that patients with recurrent metastatic endometrial cancer who took the drug had statistically significant improvement in the median progression-free survival (PFS), which is the primary endpoint of the study.
Ariad’s mTOR inhibitor ridaforolimus is an orally bioavailable analog of rapamycin. It is also known as sirolimus (Rapamune®). Sirolimus was originally developed as an antifungal drug. Since the specialists recognized this drug’s antiproliferative and antiinflammatory effects, they began to use it in organ transplant rejection prophylaxis in solid organ transplantation. Rapamycin was discovered in a soil sample from Easter Island, also known as Rapa Nui, hence its name.
In the promising interim phase 2 clinical trials, patients were randomized to receive either oral ridaforolimus, oral progestin, or chemotherapy – the latter two drugs are standard treatments for advanced endometrial cancer. The results, which were determined using RECIST (Response Evaluation Criteria In Solid Tumors) based on radiologic studies conducted every two months demonstrated significant improvement of PFS.
The adverse events of ridaforolimus included mucositis (38.2%), stomatitis (21.8%) and hypergly-cemia (27.3%). These adverse effects were expected as they are recognized as class effects of mTOR inhibitors. They affected 23.6% of patients compared to 3.8% of patients given the standard of care drugs. Based on the bad prognosis of advanced endometrial cancer, the side effects are not expected to cause any problem towards approving a drug that would extend disease-free survival in hopeless patients. Ridaforolimus has high odds of approval.
Ariad is not the first company to become interested in mTOR as a target for cancer therapy. Other drug developers preceded Ariad in this respect. The reason is that mTOR is involved in cell proliferation, angiogenesis, and metabolism – all required for cancer growth and survival. As a matter of fact, if approved, ridaforolimus will not be the first in its kind to hit the cancer market. Other Rapamycin analogs have been successfully developed, approved and marketed. They demonstrated efficacy against solid cancers and leukemia as monotherapies or in combination with chemotherapy or targeted agents. Torisel (temsirolimus) developed by Wyeth and Afinitor (everolimus) by Novartis are also rapamycin analogs targeting mTOR. Torisel is administered by intravenous infusion while Afinitor, like ridaforolimus, is given orally. So, Ariad’s drug will probably be competing with Affintor. Many scientists believe that ridaforolimus’ longer halflife gives it advantage over other mTOR inhibitors.
In 2007, Ariad and Merck signed a partnership agreement to develop Ariad’s mTOR inhibitor. The agreement provided Ariad with $75 million upfront payment and promised the firm millions of dollars in milestone payments. Three years later, Ariad found out that spending crazy money on developing this drug would limit it from developing other important drugs, especially its multikinase inhibitor AP24534. It renegotiated the agreement with Merck and a new agreement signed enabled Ariad to get back $50 million plus $19 million it had spent on the drug in 2010 with a potential of $514 million in milestone payments and over 10% royalties on global sales. The new agreement worked in both parties’ favor.
Ponatinib: An oral multi-targeted kinase inhibitor for cancers resisting available drugs. In addition to inhibiting the enzymatic activity of BCR-ABL, Ponatinib also inhibits BCR- ABL isoforms that carry mutations, which confer resistance to existing tyrosine kinase inhibitors. Among the inhibited mutation is T315I mutation for which no effective therapy exists. Ponatinib is in a pivotal phase 2 clinical trials in patients with resistant or intolerant chronic myeloid leukemia (CML) and Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Ponatinib, also known as AP24535, is being investigated in preclinical study for solid tumors.
The investigational drug is for patients who have not benefited from Gleevec, Tasigna and Sprycel. Ponatinib will have the chance to be given to patients in early disease, depending on how it performs compared to the three drugs, which would increase its revenues. The drug is expected to demonstrate efficacy on other cancers.
AP26113 is a small-molecule anaplastic lymphoma kinase (ALK1) inhibitor. The drug is being investigated for non-small-cell lung cancer (NSCLC), neuroblastoma and anaplastic large cell lymphoma (ALCL) – the cancers where ELM4-ALK exists.
1. ALK was first identified as a chromosomal rearrangement in anaplastic large cell lymphoma (ALCL). Genetic studies indicate that abnormal expression of ALK is a key driver of certain types of non-small cell lung cancer (NSCLC) and neuroblastomas, as well as anaplastic large cell lymphoma (ALCL). Since ALK is generally not expressed in normal adult tissues, it represents a highly prom- ising molecular target for cancer therapy.
It is important to note that Ariad scientists have identified multiple potent compounds that inhibit ALK both in vitro and in vivo while maintaining significant selectivity over the highly similar insulin-like growth factor-1 receptor and insulin receptor tyrosine kinase. Based on proprietary Ariad chemistry, AP26113 must be considered the lead compound in this class, potently inhibiting tumor cells that express ALK while having no effects on cells that do not express ALK. In addition, this compound is active when administered orally in vivo in animal models of lymphoma and lung cancer, with minimal effects on insulin or glucose levels. Preclinical studies demonstrated AP26113 potent inhibition of the target protein and of mutant forms that are resistant to the first-generation ALK inhibitor.
Pinpointing The Origin Of Drugs’ Resistance
Could Provide Advantage for Ariad’s Drugs over the Competition
ARIAD scientists used an assay to identify mutations in ALK that is causing resistance against Pfizer’s drug Crizotinib (PF-02341066) or to AP26113. The scientists were able to predict and pinpoint multiple mutations in ALK that confer the clinical resistance to tyrosine kinase inhibitors, such as the BCR-ABL inhibitors used in chronic myeloid leukemia (CML). Three of these ALK mutants were also tested in mouse tumor models, and in each case, Ariad’s drug AP26113 potently blocked tumor growth while Pfizer’s drug PF1066 was ineffective.
In a second study, ARIAD performed direct comparative studies on AP26113 and PF1066 in a series of ALK-dependent cell culture and in vivo models. In all models, AP26113 was at least ten fold more potent than PF1066. In addition, AP26113 exhibited 100-fold selectivity for ALK-positive cell lines compared with an approximate 10-fold selectivity for PF1066, and demonstrated excel- lent properties, including the potential for once-daily oral dosing.
Inhibition of the mutant ALK fusion gene, ELM4-ALK, with Pfizer’s experimental crizotinib has demonstrated efficacy in NSCLC harboring this mutation. Resistance to the drug, though, appears over time.
The news coming from Ariad’s pipeline at this time is supposed to stir the stagnation in the firm’s stock, a phenomenon that usually appears when developing-stage biotech firms are in the stage where errors are expected before settling on what would show the benefits outweighing the risks. The problem for investors is that the market barely considers the scientific value of the firms when deciding upon their firms’ market caps.
Ariad, is now in a much better territory than were it was months ago. The firm is walking with steady legs on the road towards bringing to the clinic a breakthrough product that is expected to be followed by a second and a third. The light has begun to show, as the drugs are nearing the end of the dark tunnel.