Status: FDA and EU filings on hold/rejected

Organizations involved:

Genta Inc. – Manuf.; R&D; Tech.

IDIS World Medicines –World mark.

Sanofi Aventis Pharmaceuticals, Inc. – Former

Sanofi Aventis S.A. – Parent; Former

University of Pennsylvania – R&D; Tech.

Washington University – R&D; Tech.

National Cancer Institute (NCI), NIH – R&D; Tech.

National Institutes of Health (NIH) – Parent

Chugai Pharmaceutical Co. Ltd. – Former

Cross ref.: See the the Antisense Drugs entry above.

Description: Genasense is an aqueous formulation of obli-mer-sen sodium, the sodium salt of a synthetic 18-oligomer (18-mer) antisense DNA phosphorothioate (1st generation-type) oligonucleotide targeted to hybridize with the initiation codon region (first 6 codons) of human Bcl-2 messenger RNA (mRNA). Oblimersen is the first therapeutic with an indication based on promoting apoptosis (programmed cell death), the first antisense drug to administered systemically, and the first new treatment for advanced melanoma in nearly 30 years.

Obli-mer-sen was designed to be an antisense drug (although many doubt it acts therapeutically through an antisense mechanism). The sequence of nucleotide bases is antisense, i.e., complementary to target nucleotide sequences but with nucleotides containing modified nucleosides, which alter the molecules properties, e.g., remaining bound to target sequences and preventing their expression (i.e., the antisense sequence binds and block complentary, targeted sequences). The DNA sequence of oblimersen is largely complementary to that of Bcl-2 mRNA, which allows oblimersen to hybridize or selectively bind to Bcl-2 mRNA (blocking Bcl-2 expression). Oblimersen contains two CpG motifs. The DNA structure of oblimersen may be represented by either of its CAS names (see “Nomenclature” section below). The molecular formula is C172-H204-N62-Na17-O91-P17-S17, and the molecular weight is 6058.28 dalton (6.058 kDa).

Nomenclature: Bcl-2 antisense drug [BIO]; oblimersen sodium [FDA USAN]; Genasense [TR]; DNA, d(P-thio)(T-C-T-C-C-C-A-G-C-G-T-G-C-G-C-C-A-T) [CAS]; augmerosen [SY]; p-thiothymidylyl-(3’to 5’)-2’-deoxy-P-thiocytidylyl-(3’to 5’)-P-thiothymidylyl-(3’-->5’)-2’-deoxy-P-thiocytidylyl-(3-->5’)-2’-deoxy-P-thiocytidylyl-(3-->5’)-2’-deoxy-P-thio-cyti-dylyl-(3-->5’)-2’-deoxy-P-thioadenylyl-(3-->5’)-2’-deoxy-P-thio-gua-nylyl-(3-->5’)-2’-deoxy-P-thiocytidylyl-(3-->5’)-2’-de-oxy-P-thioguanylyl-(3-->5’)-P-thiothymidylyl-(3-->5’)-2’-de-oxy-P-thioguanylyl-(3-->5’)-2’-deoxy-P-thio-cytidylyl-(3-->5’)-2’-deoxy-P-thioguanylyl-(3-->5’)-2’-deoxy-P-thiocytidylyl-(3-->5’)-2’-deoxy-P-thiocytidylyl-(3-->5’)-2’-deoxy-P-thio-ade-nylyl-(3-->5’)-thymidine hepta-deca-sodium salt [CAS]; 190977-41-4 [CAS RN]; G3139 [SY]; G 3139 [SY]

Biological.: Bcl-2 protein plays a central role in the process of apoptosis (programmed cell death) by blocking apoptosis. Apoptosis is a normal cellular function, eliminating aged or damaged cells, and allowing their replacement by new cells. Bcl-2 is normally found inside the mitochondrial membrane where it regulates the release of cytochrome C. Once released from the mitochondria, cytochrome C triggers the activation of caspase enzymes which ultimately result in cell death. Overexpression of Bcl-2 and reduced apoptosis are features of many tumor types, and Bcl-2 overexpression is associated with resistance to cancer treatments, including radiation, steroids, and chemotherapy. When Bcl-2 levels in a cell are elevated, apoptosis is blocked. Conversely, when Bcl-2 levels in a cell are lowered, the rate of cell death is accelerated. Bcl-2 likely exerts its apoptosis-blocking effect at a final common pathway leading to apoptotic cell death. However, the molecular mechanism by which Bcl-2 blocks apoptosis remains enigmatic. An understanding of the role of Bcl-2 in the process of apoptosis is complicated by the observation that Bcl-2 is undetectable in some cell types that undergo apoptosis.

The presence of Bcl-2 in cells renders the cells highly resistant to various chemical and physical agents. In particular, Bcl-2 renders cancer cells more resistant to chemotherapeutic agents. Various cellular and viral gene products have been identified that share a similar structure or activity with Bcl-2. However, despite the similarity of Bcl-2 to these Bcl-2-related proteins, no structural feature of the Bcl-2 protein has been related to its mechanism of regulating apoptosis.

Oblimersen has been presumed to act by antisense mechanisms. Oblimersen and other antisense oligonucleotides are essentially short (usually 30 bases or less) single-stranded synthetic DNAs having a complementary base sequence to a specific target mRNA sequence, and form a hybrid duplex by hydrogen bonded base pairing with the target mRNA, but with the nucleotides linked by a phosphorothioate (sulfur-linked) bonds rather than the usual phosphate bonds. This hybridization generally prevents translation of the target mRNA code into its protein product. The mRNA sequence expressed by the targeted gene is termed the sense sequence, and the complementary sequence, e.g., an antisense drug, is termed the antisense sequence. Inhibition of mRNA may be more efficient than inhibition of an enzyme’s active site, since one mRNA molecule gives rise to multiple protein copies.

Oblimersen may inhibit tumor cell growth by an antisense mechanism, or in a partially bis-CpG-dependent non-antisense manner, e.g., with CpG and/or other sequences inducing an immune response that weakens cancer cells. Genta asserts that downregulation of the Bcl-2 gene is the only mechanism ever “proven” for oblimersen, making it a bona fide antisense inhibitor. However, critics note that Bcl-2 upregulation results in tumor cells resistant to chemotherapy, and that nobody has proven that downregulating Bcl-2 makes cells less resistant. Ir-respective of its mechanism of action, the activity and efficacy of obli-mersen against a wide variety of tumors indicates that Genasense may be useful for treatment of a wide variety and, perhaps, most tumors.

Although designed as an antisense drug, converse to what one might expect (and presumed by its developers and others), some assert that oblimersen does not inhibit Bcl-2 expression by any known antisense mechanism. The sequence of nucleotide bases is antisense, i.e., complementary to that of Bcl-2 mRNA. This would normally be expected to cause oblimersen to hybridize or selectively bind to Bcl-2 mRNA, but this is hard to study and other mechanisms of action, e.g., related to activity of the CpG sequences of oblimersen, may be primarily or secondarily involved in its biological activities.

Companies.: Genasense was originally developed and is manu-factured by Genta Inc. Genta and Aventis Pharma (now Sanofi Aventis S.A.) formed a collaboration in April 2002, and jointly develop and market the drug in the U.S., i.e., it was to be co-marketed in the U.S. by Genta and Sanofi Aventis Pharmaceuticals, Inc. Sanofi Aventis S.A. had exclusive marketing rights outside the U.S. Aventis Pasteur merged into Sanofi Aventis S.A. in late 2004. Aventis tested Genasense in combination with Taxotere (docetaxel; a taxol-type formulation), its own $900 million/year cancer drug, before signing its deal with Genta. Chugai Pharmaceutical Co. Ltd. had originally licensed worldwide marketing rights.

The Aventis-Genta deal had potential value of $480 million for Genta (irrespective of royalties), and this was the second largest (costliest) alliance around a single pharmaceutical at the time (after the BMS deal with ImClone for Erbitux). Genta received a $135 million up-front payment, including a $75 million equity investment, and receives the remaining $345 million as milestone payments. Aventis assumed most development costs, and Genta projected that Aventis could spend another $390 million to cover development and commercialization costs. Aventis paid for Genta’s U.S. sales force, and the two companies split U.S. sales of Genasense evenly. Genta was to receive royalties on sales in the “comfortable double-digits” (i.e., over 10%).

The National Cancer Institute (NCI), National Institutes of Health (NIH), funded and conducted preclinical studies with oblimersen in July 1996. In June 1998, Genta and NCI concluded a Collaborative R&D Agreement (CRADA) for further development of the drug.

On Nov. 8, 2004, with several failures in clinical trials (see Trials section below) and major problems with the initial FDA filing for melanoma, Sanofi/Aventis Pharma (became Sanofi Aventis in late 2004) announced it was withdrawing from its collaboration with Genta. On Nov. 8, 2004, the agreement was terminated, with neither party having any obligation to the other. Genta assumed responsibility for an ongoing European Phase II trial of Genasense in combination with Taxotere docetaxel to treat hormone-refractory prostate cancer.

Genta now holds all marketing rights.

In March 2007, Genta concluded an agreement granting IDIS World Medicines worldwide rights to distribute Genasense on a named patient/compassionate use basis.

FDA class: Drug NDA

Status: Genta completed its New Drug Application (NDA 21-649) on Dec. 8, 2003 and it was accepted for filing on Feb. 6, 2004 for approval of Genasense in combination with dacar-ba-zine for the treatment of patients with advanced malignant mela-noma. The NDA was submitted under the fast-track program (allowing incremental filing of portions of the application), and Genta requested and received priority review (with a 6 month PDUFA approval decision target date of June 8, 2003). Genasense received orphan drug designation in August 2000. If approved, Genasense would be the first new therapeutic in 20 years for advanced melanoma.

Some researchers, analysts, and even the current CEO of Genta have noted that Genasense could have reached the market sooner, perhaps, as soon as 1998 or 1999; and blame the company for ineffective and slow development. Commercial development of Genasense begin about 1995.

On April 20, 2004, Genta and Aventis implemented an Expanded Access Program (EAP) in the U.S. with Genasense in combination with dacarbazine for patients with advanced (Stage IV and unresectable Stage III) melanoma who have not previously received chemotherapy.

On May 4, 2004, the Oncologic Drugs Advisory Committee (ODAC), FDA, voted 13-3 against approval of Genasense, voting that the available evidence regarding Genasense did not provide substantial evidence of effectiveness, as measured by response rate and progression-free survival, to outweigh the increased toxicity of administering Genasense for the treatment of patients with metastatic melanoma who have not received prior chemotherapy. See the Trials section below. Advisory committee’s recommendations are not binding, but FDA approvals/denials usually follow their recommendations. The committee voted 11-5 that Genasense plus dacarbazine showed a difference in response rate from dacarbazine in patients with metastatic melanoma. However, the committee then voted 12-4 that the pivotal trial did not conclusively show a “real effect” on progression-free survival. It appeared that Genta and Aventis (now Sanofi Aventis) would have to conduct a confirmatory study to validate either survival or progression-free survival as the primary endpoint. As has become common in such circumstances, following the advisory committee meeting, Genta became the target shareholder lawsuits alleging prior failure to release sufficient information about Genasense’s trials.

On May 13, 2004, Genta withdrew its NDA for Genasense, ended the Genasense expanded access program for melanoma, and reduced its staff by 45%. Genta then focused on finishing development of Genasense, starting with further analyses of its clinical trials, and subsequently initiated new trials.

On Dec. 2005, Genta completed the refiling of the NDA for Genasense use in combination with fludarabine and cyclophosphamide as treatment for patients with relapsed or refractory chronic lymphocytic leukemia (CLL). The NDA was submitted under fast track (six months target action date) and accelerated approval designations, and has also received orphan designation. The NDA contained safety and efficacy data from a Phase I/II trial of Genasense in ~40 patients, and a randomized controlled Phase III study of 241 patients who received fludarabine and cyclophosphamide with or without Genasense. These data were supplemented by safety data derived from ~1,000 additional patients who have received Genasense in other clinical trials. Accelerated approval will require the Genta to conduct a post-approval (Phase IV) confirmatory study. In Oct. 2006, FDA noted that submission of the new information by Genta comprised a major amendment to the NDA, and FDA elected to extend the review period for 90 days to Jan. 29, 2007.

On Sept. 6, 2006, the Oncologic Drug Advisory Committee, FDA, voted against recommending approval of Genasense. FDA staff presentations had questioned whether Genasense provides any substantial improvement over chemotherapy. FDA in its summary stated that although trial results showed improvements with Genasense, which did not reach statistical significance, the improvements are “of questionable clinical significance,” with a complete response to Genasense treatment of 17%, compared with a 7% response rate for chemotherapy alone. Also, the median survival rate on a combination of Genasense and chemotherapy was 33.8 months, while the group on chemotherapy alone had a median survival rate of 32.9 months.

In Oct. 2006, Genta received a Special Protocol Assessment (SPA) with FDA for a trial of Genasense in chemotherapy-naive patients who would randomly receive fludarabine plus rituximab (Rituxan; see related entry) with or without Genasense.

On Dec. 15, 2006, FDA sent Genta a non-approvable letter regarding its NDA for Genasense plus chemotherapy for treating chronic lymphocytic leukemia. The company filed a formal appeal in April 2007. Genta subsequently announced initiation of a new Phase III trial with Genasense (see the Trials section below)

Genta noted, “It is puzzling that the Office [FDA] would deny approval to a drug that met both its primary as well as a key secondary endpoint, especially since these findings were observed in the only randomized controlled trial that has ever been conducted in patients with relapsed CLL. These findings were statistically significant, and they represent clear benefit to patients.” Genta asserts that FDA used an incorrect statistical analysis for melanoma starting back in 2004 and that this led to discrediting of a trial show improved. The appeal also notes that “Complete response confers clinical benefit in CLL. By definition, a complete response requires elimination of all evident disease, normalization of blood counts, and resolution of symptoms. -- Complete responses -- the primary endpoint of the Genasense trial -- were more than doubled if the chemotherapy regimen included Genasense compared to chemotherapy used alone -- an increase that was statistically significant. -- The median duration of complete response exceeded 3 years, at least 50% longer, if the chemotherapy regimen included Genasense - a clinically meaningful and statistically significant increase in a prospectively specified secondary endpoint. -- The Genasense study is the only randomized controlled trial ever conducted in this population. -- The number, type, and severity of adverse reactions encountered with Genasense were comparable to other leukemia drugs, which are managed by specialists.”

On Jan. 3, 2006, Genta filed and on Feb. 1, 2006, the European Union (EMEA) accepted Genta’s MAA filing for Genasense plus dacarbazine for treatment of patients with advanced metastatic melanoma. The data submitted included 24 months of follow-up demonstrating a positive trend in all endpoints, compared to the U.S. filing, which had only six months of data. However, EMEA subsequently issued a 180-day List of Outstanding Issues noting problems with the filing (clinical trials).

In April 2007, the Committee for Medicinal Products for Human Use (CHMP), European Medicines Agency (EMEA) issue a negative opinion on the Genasense MAA for patients with advanced melanoma. A final decision (most likely rejection) was expected in 4-6 months. However, in July 2007, as a result of the requested re-examination, EMEA reaffirmed its negative opinion for approval of Genasens and indicated that positive findings observed in the Phase III trial of Genasense should be confirmed in an additional study (i.e., another trial is required). Genta has already announced its intent to conduct such a study, known as AGENDA.

Tech. transfer: Dr. S. Korsmeyer, Washington University, and collaborators first sequenced the Bcl-2 gene. Genta presumably has taken a license to related patents, including U.S. 5,622,852 and 5,834,209, “Bcl-x/Bcl-2 associated cell death regulator;” 5,691,179, “Cell death regulators,” and related patents assigned to Washington University.

Genta has licensed U.S. 5,831,066, “Regulation of bcl-2 gene expression,” by Dr. J.C. Reed, assigned to the University of Pennsylvania. This includes claims covering Genasense and other Bcl-2 antisense oligonucleotide analogs and use for inhibiting tumor growth.

Genta has nonexclusively licensed fundamental antisense phosphorothioate (1st generation-type antisense technology) from the National Cancer Institute (NCI), National Institutes of Health (NIH). This includes U.S. 5,276,019, “Inhibitors for replication of retroviruses and for the expression of oncogene products,” Jan. 4, 1994, assigned to NIH, with claims broadly describing antisense phosphorothioates targeted to specific gene sequences and their use to halt expression of targeted genes for therapeutic and other purposes. Related NIH patents include 5,264,423 and 5,286,717. Previously, antisense oligo-deoxy-ribo-nucleotides had limited utility because they were readily degraded in vivo by nucleases or required excessively high concentrations to elicit therapeutic antiviral effects. Phosphorothioate oligonucleotide analogs are more effective, resistant to degradation and hybridize with complementary sequences much more efficiently. [However, second and later generation oligonucleotides offer improved resistance to degradation and improved pharmacodynamics].

As a licensee of the NCI/NIH phosphorothioate patents, Genta is involved in an ongoing U.S. Patent and Trademark Office (PTO) interference action concerning first generation phosphorothioate antisense oligonucleotide patent applications assigned to the University of Massachusetts (UMass), which have been exclusively licensed by Hybridon, Inc. (which has licensed antisense technology from the Worcester Foundation), and three patents issued to NIH. See the CMV Antisense Drug (fomivirsen sodium) entry below for further information.

Trials: In various clinical trials, Genasense has doubled tumor response rates, providing a significant, e.g., 60%, improvement in progression-free survival, and it has improved overall survival by about 25% in patients who were refractory to other treatment. However, in the case of melanoma, conventional therapy only offers an ~7% improvement in survival, so further improvements from addition of Genasense may not offer much of an absolute improvement in survival and would be hard to measure. Adverse events are significantly higher in Genasense-treated patients include (but were not limited to) thrombocytopenia, nausea, fever, fatigue, back pain, weight loss, dehydration, and intravenous catheter complications.

The recent NDA for Genasense was primarily based on two separate clinical trials. The first was a Phase I/II trial that demonstrated the safety and activity of the drug used as a single-agent in 40 patients who had received extensive anti- leukemic therapy. The second trial was a randomized, multicenter, multinational trial in which 241 patients with relapsed or refractory CLL received standard chemotherapy (fludarabine plus cyclophosphamide) with or without Genasense.

In Nov. 2004, Genta reported mixed results from the pivotal Phase III trial of Genasense in patients with chronic lymphocytic leukemia (CLL). This trial studied whether the addition of Genasense to standard treatment (cyclical treatment with a combination of two chemotherapy drugs, fludarabine and cyclophosphamide) was superior to standard treatment alone in patients who have previously received and have relapsed from other therapies. The primary endpoint, an increase the proportion of patients who achieved a complete or nodular partial remission (CR/nPR), was met. However, there was no benefit observed in patient survival and time to disease progression. Aventis had access to these the top-line results before it backed out of Genasense development.

In Oct. 2005, further results were reported from the Phase III trial The trial met its primary endpoint. Addition of Genasense increased the proportion of patients who achieved CR/nPR from 7% in the Flu/Cy-only arm to 17% in the Genasense arm (p = 0.025). The duration of CR/nPR was significantly longer in patients treated with Genasense compared with patients who received Flu/Cy only (median = not reached vs. 22 months, respectively; p = 0.03). At last analysis, the duration of complete clinical benefit was 383+ patient-months in the Genasense group compared with 136+ months in the Flu/Cy-only group. In addition to achieving the prospectively defined, intent-to-treat primary endpoint, patients in the Genasense group who were protocol-defined as “non-refractory” to fludarabine (comprising more than 40% of the total population) achieved a four-fold increase in CR/nPR (25% [13/51] vs. 6% [3/50]; P = 0.016); increased time-to-progression (median = 12 months. vs. 10 months; P = N.S.); and increased overall survival (median not reached but exceeding 39 months. vs. 33 months; P = 0.05). These result appeared to support the efficacy of Genasense for refractory CLL.

Another randomized open-label Phase III trial (GM-301) in malignant melanoma submitted to support approval compared Genasense plus standard treatment [dacarbazine (DTIC) administered once every 3 weeks] to standard treatment alone in patients with advanced-stage disease who had not previously received chemotherapy (drug-naive patients). This was the largest randomized trial in patients (n = 771) ever conducted for advanced melanoma. The trial did not meet its primary endpoint of statistically significant improvement in overall survival (decreased mortality). Patients in the combination arm had a median survival of 274 days compared to 238 days for dacarbazine alone (p=.18). The firm hired by Genta for independent review of trial results failed to confirm a single complete response, including five the company had previously announced as complete responses. [At the time, the belief that Genasense resulted in these complete responses may have had a small part in helping Aventis fight off a hostile takeover bid from Novartis AG]. Patients who received Genasense plus dacar-bazine showed other improvements – a 51% improvement in median progression-free survival (74 days vs. 49 days; p= .0003); an improvement in durable response rate of ≥6 months, (13 patients vs. 5 patients); and a 72% increase in overall anti-tumor response rate (11.7% vs. 6.8%; p=.019).

FDA staff and some advisory committee members expressed concerns about missing data, and that combination patients were evaluated slightly later than those taking dacarbazine alone, something which FDA viewed as potentially leading to false positive results in such a large study. An FDA representative stated, “Approval for a melanoma application requires substantial evidence of efficacy. Review of the literature has not shown a correlation of improvement in PFS [progression-free survival], [time to tumor progression] or [relative risk] with an improvement in survival...Survival was not improved and toxicity was increased.”

During the FDA advisory committee meeting that considered Genasense, Aventis presented additional information on complete responders that were not part of the original NDA submission, and that have not been confirmed by the FDA. Six additional patients were identified who achieved complete responses in the follow-up period in the Genasense plus dacarbazine group, yielding a total of 11 complete responses. No additional complete responders were identified in the dacarbazine alone group. In another randomized clinical trial, patients receiving Genasense combined with dacarbazine (n=371) were compared to those receiving dacarbazine alone (n=360). The most frequent serious adverse event occurring in ≥5% of patients was fever (5.9% vs. 3.1%, respectively); the most frequent Grade 3 or 4 adverse events occurring in greater than or equal to 5% of patients were neutropenia (21.3% vs. 12.5% respectively), thrombocytopenia (15.6% vs. 6.4%), leukopenia (7.5% vs. 3.9%), anemia (7.0% vs. 4.7%), and nausea (7.0% vs. 2.5%).

In Jan. 2006, Genta initiated a trial of a new formulation of Genasense administered by intermittent subcutaneous injection. The formulation is five-fold more concentrated than that used in other clinical trials.

In Feb. 2006, Genta presented new analyses that confirmed the major efficacy variables from the the randomized pivotal Phase III trial of Genasense plus chemotherapy in patients with advanced metastatic melanoma. This was the largest randomized trial ever conducted in patients with advanced melanoma. The trial randomly assigned 771 patients to receive standard chemotherapy using dacarbazine with or without Genasense. Prior to randomization, patients were stratified on the basis of performance status, sites of metastatic disease, and baseline levels of serum lactate dehydrogenase (LDH), a marker for poor prognosis in melanoma patients. Consistent with prior studies, multivariate analysis confirmed that each of the three stratification factors was significantly correlated with survival in the Genasense trial, whether examined alone or in a Cox multivariate model. However, LDH was the only factor that showed a statistically significant interaction with treatment. Analysis also showed that Genasense was significantly superior to chemotherapy alone in major efficacy variables after accounting for prognostic factors. The maximal benefit of Genasense was observed in patients without elevation in baseline LDH, a group that comprised approximately two-thirds of the study population, or more than 500 patients. The analysis of this trial with a minimum follow-up of 24 months on all patients comprised the basis of Genta’s MAA seeking approval of Genasense of advanced metastatic melanoma. An earlier analysis of this trial based on a minimum follow-up of 6 months comprised the basis of a NDA that was withdrawn by Genta in 2004.

In Sept. 2006, final results from the Genasense pivotal Phase III trial were published online in the Journal of Clinical Oncology. The article included data from a prospectively defined analysis that evaluated 24-months of minimum follow-up on all patients.

In Nov. 2006, Genta initiated a pilot trial of Genasense combined with Abraxane (paclitaxel) and Temodar (temozolomide) for first-line treatment of advanced melanoma. This was is the first follow-on study to Genta’s randomized Phase III trial of Genasense plus dacarbazine.

In Feb. 2007, Genta reported preliminary results from a Phase II study of Genasense Injection plus chemotherapy in patients with advanced prostate cancer, with Genasense plus docetaxel and docetaxel alone showing similar efficacy (i.e., Genasense not significantly effective). This randomized open-label trial was conducted by the European Organisation for Research and Treatment of Cancer (EORTC).

In summer 2007, Genta is initiating a new randomized, controlled, ~300-patient, Phase III trial of Genasense in patients with advanced melanoma in Europe, Australia, and North and South America. The trial is designed to expand evidence for the safety and efficacy of Genasense combined with dacarbazine chemotherapy in chemotherapy-naive patients (i.e., first-line use). The study is prospectively targeting patients using a biomarker that identified patients who derived maximal benefit in a preceding trial of Genasense, including significant increases in overall and progression-free survival.

Genta, on its own, and/or under its Collaborative Research and Development Agreement (CRADA) with the National Cancer Institute (NCI), has been or is being tested in non-randomized clinical trials in: small-cell lung cancer; non-small cell lung cancer; acute myeloid leukemia; small-cell lung cancer; breast cancer; prostate cancer; liver cancer; renal cancer; non Hodgkin’s lymphoma; multiple myeloma; colon cancer; pancreatic cancer; pediatric solid tumors; and Waldenstrom’s tumors.

Genasense remains in clinical trials for non-small-cell lung, small-cell lung, and prostate cancers. However, in light of prior failures in trials, many are pessimistic about the future of Genasense (and Genta, since this is the company’s only major product in development). Genasense has shown preliminary efficacy in combination with Rituxan from Genentech.

Medical: Genasense potentiates the cancer-killing activity of standard cancer chemotherapy. The side-effects of Genasense do not generally overlap with current adverse effects of current methods of cancer treatment. Thus, alteration in either the dose or schedule of conventional therapy is not expected to be required for use Genasense.

Genasense is given as a continuous intravenous infusion using a Hickman device and portable pump, typically over the period of 5-7 days, followed by 2 weeks off. In trials, this 3-week cycle was repeated for up to 12 months.

Market: Since Genasense may be effective against many, if not most, cancers in combination with chemotherapy drugs, it may have blockbuster sales potential. However, it will first have to show efficacy to receive approvals.