May 15, 2014 (Vol. 34, No. 10)

Selective, targeted small molecule drug candidates are moving through the clinical development pipeline in a range of disease indications.

While the current generation of small molecule drugs in clinical trials share some key advantages with small molecule therapeutics already on the market, such as oral bioavailability and less complex synthetic processes compared to biopharmaceuticals in general, many of these new compounds are first-in-class drugs and have novel targets and mechanisms of actions.

Redox drugs, for example, which target the mitochondria and intervene in electron transfer pathways to correct disorders of energy regulation and metabolic control, offer a therapeutic strategy with potential applications across a range of diseases including inherited mitochondrial disorders affecting pediatric patients and neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Parkinson’s, Huntington’s, and Alzheimer’s disease.

Edison Pharmaceuticals’ most advanced redox drug candidate, EPI-743 (Vincerinone®), recently gained fast track designation from the U.S. FDA for the treatment of Friedriech’s ataxia, an inherited mitochondrial disease in which a defect in the frataxin gene impairs the function of the mitochondrial respiratory chain, which negatively affects cellular energy metabolism.

The company’s chairman and CEO, Guy Miller, M.D., Ph.D., describes a redox therapeutic as “a molecule that can stably undergo oxidation/reduction and transfer and receive an electron between two points in space.” In addition, the molecule can “accomplish this in a reversible/catalytic manner.”

EPI-743 is an orally administered drug that is able to cross the blood-brain barrier. It does not target or up- or down-regulate a particular enzyme, but instead is a co-factor for key enzymes involved in cellular metabolic control. It exerts its therapeutic effect by augmenting endogenous glutathione biosynthesis, thereby optimizing a series of electrochemical reactions in the mitochondria.

The compound is in Phase IIb/III placebo-controlled clinical trials in Leigh syndrome and Freidriech’s ataxia, and in exploratory Phase IIa studies in cobalamin C defect, Pearson syndrome, and undiagnosed disorders of oxidation-reduction. Edison entered into an estimated $4.295 billion strategic alliance with Dainippon Sumitomo Pharma earlier this year.

“We believe there is common biochemistry between children with inherited mitochondrial diseases and adults with neurodegenerative diseases,” says Dr. Miller, with similar defects in mitochondrial-based electron handling processes. The next phase of development for its redox therapeutics will focus on the role of mitochondrial dysfunction in neurodegenerative disorders and diseases of aging.

Omeros reported positive data from a Phase IIa trial in schizophrenia with its OMS824 phosphodiesterase 10 (PDE10) inhibitor at increased drug exposure, in which the compound is being evaluated in combination with patients’ usual antipsychotic drug regimens. The ability to block PDE enzyme activity in the brain may have therapeutic benefit in other disorders as well.

Omeros is preparing to initiate a Phase II trial with OMS824 for the treatment of cognitive impairment in patients with Huntington’s disease. The company is also developing small molecule agonists and antagonists for orphan G-protein coupled receptors (GPCRs), which it identifies in screening campaigns using its high-throughput cellular redistribution assay.

The lead therapeutic candidate in development by Receptos is RPC1063, an orally delivered sphingosine 1-phosphate 1 receptor (S1P1R) small molecular modulator. Earlier this year, the company began enrollment of Phase III of the Phase II/III RADIANCE trial in relapsing multiple sclerosis. This study will compare two doses of RPC1063, 0.5 mg and 1.0 mg, to interferon beta-1a in 1,200 patients. Receptos has also begun enrollment for a Phase II study of the compound in patients with ulcerative colitis.

Cellceutix announced initiation of a Phase II/III clinical trial of Prurisol™, an oral small molecule agent for the treatment of psoriasis. The drug, manufactured through a five-step process, acts via immunomodulation and reduction of psoriasis-associated RNA induced by stress (PRINS), a noncoding RNA. Prurisol showed efficacy in animal models in both induced psoriasis and in a xenograft model with human psoriatic tissue.

Edison Pharmaceuticals’ lead drug candidate, EPI-743, is a member of the para-benzoquinone chemical class whose mechanism relies on two-electron reversible transfer. EPI-743 works through redox control—critical to the regulation of cellular energy metabolism.

A No-Nonsense Approach

As PTC Therapeutics completes enrollment this year of a confirmatory Phase III trial in children with nonsense mutation Duchenne muscular dystrophy (nmDMD) with its lead compound ataluren (PTC124®), the company is also planning to initiate a confirmatory Phase III trial in nonsense mutation cystic fibrosis (nmCF) and to launch a proof-of-concept study for a third indication.

Funding to support this expanded clinical development of ataluren comes from PTC’s successful IPO in June 2013. This IPO grossed approximately $144.4 million, and a follow-on offering in February 2014 grossed an additional $126.5 million.

PTC developed an integrated set of proprietary technologies based on RNA biology for the discovery of small molecules that target post-transcriptional control processes. Two of these technologies are nonsense suppression and alternative splicing.

Ataluren is a new chemical entity that targets a novel mechanism of action. It prevents a premature termination event during translation of the mRNA transcript, allowing the ribosome to insert an amino acid at the site of the premature stop codon, or nonsense mutation, and produce a full-length protein.

Among the thousands of inherited monogenic diseases, a subset of patients with many, if not most of these disorders, has a nonsense mutation in the protein-coding region that interrupts protein production, causing the disorder, explains Stuart W. Peltz, Ph.D., CEO. Overall, about 10–15% of patients with these single gene defects have nonsense mutations, including 13% of children with DMD, 10% of cases of CF, and 70% of patients with mucopolysaccharidosis type I (MPS-1).

Ataluren demonstrated activity in initial Phase IIb trial in DMD as measured by the six-minute walk test—and larger effects in patients with more rapidly advancing disease. The Phase III trial planned in cystic fibrosis will evaluate the ability of the drug to affect pulmonary function and reduce disease exacerbations.

A Phase I clinical program initiated for the drug candidate targeting spinal muscular atrophy (SMA) is under way in collaboration with PTC’s development partners, the SMA Foundation and Roche. The approximately 20,000 patients with SMA, an autosomal recessive genetic disorder, have a mutation in the SMN1 gene, affecting production of a functional SMN protein. A nearly identical gene, SMN2, produces an mRNA that undergoes post-transcriptional splicing, resulting in removal of an exon that is present in the normal SMN1 gene transcript.

The protein produced from the SMN2 gene is more unstable and is rapidly degraded. The oral compounds developed utilizing PTC’s alternative splicing technology intervene in the post-transcriptional splicing of the SMN2 mRNA to retain the exon that would have been excised, yielding a normal SMN protein.

Scientists at PTC Therapeutics are developing small molecule therapeutics that target post-transcriptional control processes. Two of the technologies that have led to drug candidates in clinical testing are nonsense suppression and alternative splicing.

Cancer in the Crosshairs

Endocyte’s Phase IIb TARGET trial indicate that the company’s EC145 (Vintafolide)/docetaxel combination, a vinca alkaloid chemotherapeutic agent, shows promise. The drug is targeted to the folate receptor expressed on cancer cells but not on most noncancerous cells. It was associated with a statistically significant improvement in progression-free survival in patients with non-small cell lung cancer (NSCLC).

Endocyte’s small molecule drug conjugate (SMDC) technology with companion imaging agents first identifies the folate-expressing tumor and then targets the chemotherapeutic payload to these cancer cells. The conjugated anticancer drug is taken up by the cells via endocytosis.

In addition to the TARGET trial in patients with NSCLC, vintafolide is being evaluated in the Phase III PROCEED study, in women with platinum-resistant ovarian cancer, and in the Phase II PRECEDENT trial, which is comparing vintafolide and pegylated liposomal doxorubicin (Doxil) to Doxil alone in women with platinum-resistant ovarian cancer.

Later this year, a study of vintafolide is planned in women with triple-negative breast cancer. The development and commercialization of the drug is part of a $1 billion partnership between Endocyte and Merck.

Array BioPharma plans to enter Phase III clinical development with ARRY-520 for the treatment of multiple myeloma by mid-year. The compound is a targeted inhibitor of kinesin spindle protein (KSP), a key factor in mitotic spindle formation, and promotes apoptosis in proliferating cells. The company believes the selective KSP inhibitor may preferentially act on hematopoietic versus epithelial cells.

Galapagos presented preclinical study results for its small molecule ephrin receptor kinase inhibitor GLPG1790 in a xenograft model of triple-negative breast cancer. The company believes the selective inhibitor of the ephrin receptor kinase family could also have a therapeutic role in melanoma and pancreatic, ovarian, prostatic, and colorectal cancers. Galapagos is also shepherding GLPG0634, an orally available inhibitor of JAK1 tyrosine kinase, through Phase IIB clinical studies for the treatment of rheumatoid arthritis and Crohn’s disease.

Karyopharm Therapeutics’ oral small molecule Selective Inhibitors of Nuclear Export (SINE) compounds inhibit the nuclear export protein XPO1, interfering in the transport of proteins out of the nucleus. The company designed its lead drug candidate KPT-330 (Selinexor) to block transport out of the nucleus of tumor suppressor proteins, promoting apoptosis of cancer cells.

Karyopharm has three ongoing Phase I trials with Selinexor in advanced hematologic malignancies, solid tumors, and sarcomas. The company has presented preliminary clinical data in study patients with metastatic colorectal cancer, which included tumor biopsy analyses showing that in tumor lesions that shrunk, “Selinexor induced nuclear localization of the tumor suppressor proteins p53 and/or FOXO1.” Other results were reduced proliferation rates and increased apoptosis levels.

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