On October 29, Genta reported that Genasense failed to meet one of the Phase III trial’s co-primary endpoints: a statistically significant benefit in progression free-survival in melanoma patients. The antisense drug also failed to meet any of the study’s currently evaluable secondary endpoints. Genta CEO, Raymond P.Warrell Jr., M.D., said that this would preclude the company’s submission of a regulatory application this year.
Further assessment of the data will certainly impact the strategic direction of Genasense. The drug has been in clinical trials for melanoma and chronic lymphocytic leukemia (CLL) since 1995 in the U.S., Europe, and Australia and has yet to win approval for either disease.
Genta isn’t the only company to have experienced late-stage antisense drug failures. To date only Isis Pharmaceuticals, originator of antisense technology, has successfully introduced such a drug. Vitravene for cytomegalovirus retinitis was launched over 20 years ago. Yet companies and investors remain committed to antisense therapeutic development.
Stanley Crooke, M.D., Ph.D., Isis Pharmaceutical’s CEO and board chairman, remains the technology’s greatest champion. In his introduction to a 2008 book on antisense technology he says that despite logarithmic progress in advancing and understanding antisense technology, “the process of converting the technology to therapeutically important, commercially successful, and systemically administered new medicines has encountered substantial disappointments.” Dr. Crooke also noted, however, that great progress and significant knowledge about these molecules has accumulated and the field has reached “the end of the beginning.”
Where Antisense Has Failed
Genasense inhibits production of Bcl-2, a protein made by cancer cells that is thought to block chemotherapy-induced cell death. This hard-luck drug has hit the wall before: In December 2006, FDA issued a nonapprovable letter for Genasense in CLL. Then in a response issued to an appeal filed by Genta in December 2008, FDA’s CDER concluded that the new information submitted by the company in its amended NDA was insufficient. It recommended that the firm conduct a confirmatory clinical trial.
Other antisense drugs that have failed clinical trials include MGI Pharma (bought by Eisai in 2007) and MethylGene’s MG98, a DNA methyltransferase inhibitor for advanced myelodysplasia or relapsed/refractory acute myeloid leukemia. Isis too has had a couple of misses with its antisense technology. Affinitak, an inhibitor of the protein kinase C-alpha for non-small-cell lung cancer, and Alicaforsen, an anti-ICAM-1 antisense oligo for Crohn’s disease, did not meet clinical expectations. ICAM-1 is a molecule believed to play a role in intestinal inflammation. Isis continues to develop the drug for ulcerative colitis, and in May, it received orphan drug designation from the EMEA for pouchitis, or inflammation of a surgically created pouch following removal of part of the large intestine.
Candidates Showing Some Promise
Isis has 19 oligonucleotide-based drugs in development on its own and with partners including Eli Lilly, Bristol-Myers Squibb, Johnson & Johnson, and Genzyme in cardiovascular, metabolic, and neurodegenerative diseases. The company has no apparent need to raise cash, projecting that its 2009 year-end balance will be greater than $550 million. It ended the year’s second quarter with $637.5 million in cash. From its inception, Isis’ strategy has been to license its drugs prior to Phase III studies.
In May of this year Isis and Genzyme reported that their Phase III trial of mipmersen in patients with homozygous familial hypercholesterolemia met its primary endpoint, with a 25% reduction in LDL cholesterol after 26 weeks of treatment versus 3% with a placebo.This study also met each of its three secondary endpoints of reduction in apolipoprotein B, total cholesterol, and non-HDL cholesterol. Of the 34 patients treated with mipomersen, 28 completed the study, and one patient discontinued due to increased liver enzyme levels.
While the results should support approval for niche use in patients with this rare disorder, noted JP Morgan analyst Geoff Meacham, safety remains a key concern as the companies seek to expand its use to larger populations. Mipomersen is a second-generation antisense nucleotide molecule that targets mRNA for apolipoprotein B and can be administered as a weekly injection. Chemical changes enable these antisense oligos to resist enzymatic breakdown, allowing less frequent administration.
Mipomersen has already generated money for Isis, which is developing it in a 50-50 collaboration with Genzyme. Genzyme agreed last year to pay Isis $175 million and buy 5 million Isis shares for $150 million to license the drug. The companies expect to file for approval in 2010.
In October Isis announced positive results from a Phase II study evaluating the safety and efficacy of ISIS 113715 in patients with type 2 diabetes. ISIS 113715 is an insulin sensitizer that reduces the expression of protein tyrosine phosphatase-1B. In addition to lowering blood glucose, ISIS 113715 also caused statistically significant and clinically meaningful reductions in LDL cholesterol. A tendency toward weight loss was also observed.
And in more positive news, Antisense Therapeutics says that Phase IIa study results for ATL/TV1101 showed that the drug significantly reduced the number of new active lesions in patients with relapsing-remitting multiple sclerosis taking the drug every eight weeks as compared to placebo. ATL/TV1101 was originally developed by Isis and has been licensed to TEVA by Antisense.
Is Antisense Where It Needs to Be?
In anticipation of ongoing therapeutic development, oligonucleotide manufacturers have ramped up production capabilities. In 2008, Agilent purchased DowPharma's nucleic acid medicines business, saying that the primary driver of this move was the rapid growth in the nucleic acid therapeutic market, driven by strong investment and collaborations. The number of publicly disclosed oligonucleotide therapeutic programs almost doubled in five years, from 121 in 2002 to 213 in 2008, according to Agilent.
“We have addressed one issue after another and have made thousands of modifications to antisense molecules, and these days, we make much better molecules,” Dr. Crooke told GEN. “About $200 million and 10 years were spent in identifying second-generation chemistry: the 2 prime methoxyethyl chimeric antisense drugs. These second-generation drugs are less inflammatory, more potent, and can be administered less frequently and via several routes.”
Dr. Crooke said that 20 years of accumulated knowledge is manifest in where the technology is now. “Antisense is exactly what it ought to be."