10.2.0 CURRENT RESEARCH, TESTING AND CERTIFICATION OF NEW DRUGS AND TREATMENTS IN THE U.S. AND ABROAD

When a company is ready to proceed to clinical trials, it files an Investigational New Drug Application (IND) with the Food and Drug Administration (FDA). Most clinical trials are designated as phases I, II, or III, and sometimes IV based on the type of questions that the study is seeking to answer.

Study Phases

• In Phase I clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
• In Phase II clinical trials, the study drug or treatment is given to a larger group of people (100-300) to evaluate safety, optimal dose, and may include some information on the drug’s effectiveness. Most drugs that enter phase II studies do not progress on to phase III studies. This is because the drug is being tested in more people for a generally longer period of time so lack of effectiveness and a better picture of the effectiveness emerges.
• In Phase III studies, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
• In Phase IV studies, the drug is already on the market for a particular indication, but is now being tested to answer questions about sub-populations of the same condition it is approved to treat, or for a different indication, use, or disease.

The testing of new drugs is a long process that typically takes about 12 years from pre-clinical testing to FDA approval and marketing to the general public.

Fast Track Status:

A drug can be granted fast track status by the Food and Drug Administration to help facilitate the development and to expedite the review process of new drugs that have the potential to address an unmet medical need for serious or life-threatening conditions such as hepatitis C.

Orphan Drug Status:

A status given to a certain drug by the Food and Drug Administration to encourage the development of drugs that are necessary, but are too expensive or unprofitable to develop under regular circumstances. Drugs being developed to treat orphan diseases (low prevalence in the population) offer tax reductions and marketing exclusivity for the drug manufacturer (up to 20 years).

For more information about clinical trials for the treatment of hepatitis C go to www.clincaltrials.gov.

DAA Combinations

HCV Inhibitors

Drugs ( General)

Interferons

Vaccines in Development

Anti Cancer Drugs

Adjunct Therapies

Clinical trials on Hold

Clinical Trials that Have Been Cancelled

Years

On November 17 2009, InterMune announced that an independent data monitoring committee recommended the company stop testing the therapy in the RG7227 900 milligram dosage given once every 12 hours after three patients had elevated levels of ALT, a liver enzyme.

EASL 2010: A small study using ritonavir (100 mg) to boost danoprevir (200 mg) both given twice a day achieved 100% undetectable HCV RNA after 15 days and was generally well-tolerated. Based on these findings an additional two study arms of prior complete non-responders will be retreated with danoprevir, ritronavir, PEG/RBV for 12 weeks. A larger study titled INFORM-3 is being planned that will include ritonavir.

On October 7th, 2010, Genentech announced that it had purchased the full rights to Danoprevir from Intermune. (October 11, 2010)

On July 28th, Vertex announced that it was on track to complete the telaprevir FDA application in the second half of this year. (July 30, 2010)

Studies were announced that will assess multiple doses of ABT-333 for a 3-day period followed by an additional 26 days with ABT-333, pegylated interferon/ribavirin. This study will be followed by a triple combination study of ABT-333 in combination with pegylated interferon plus ribavirin for 12 weeks followed by an additional 36 weeks of pegylated interferon plus ribavirin. All participants are HCV genotype 1 treatment-naive patients. (June 30, 2010)

On March 12, 2009, Vertex announced that it had completed acquisition of Virochem and will be developing Virochem’s HCV polymerase inhibitors in combination with their drug and will study Virochem’s drugs in combination with pegylated interferon plus ribavirin. (March 13, 2009)

EASL 2010: Results from a small study of 20 genotype 2 and 3 patients who did not achieve an SVR in a previous course of interferon therapy and who were retreated with RG7128 and Pegasys/ribavirin found that 90% of the patients treated for 48 weeks achieved an SVR compared to 67% for the group who were treated for 24 weeks.

Interim results from the PROPEL study were released—in the study HCV genotype 1 and 4 patients were treated with RG7128 (with pegylated interferon/ribavirin) or pegylated interferon/ribavirin (without RG7128). More than 80% of the patients in the RG7128 arm had undetectable viral load compared to less than 50% in the group that did not receive RG7128 after twelve weeks of treatment. (June 30, 2010)

(PF-00868554)

Recently, Achillion announced a placebo-controlled phase IIa study to evaluate the safety, tolerability and antiviral activity of ACH-1625 in conjunction with pegylated interferon alfa-2a and ribavirin. The study will evaluate Genotype 1 patients after 4 and 12 weeks of dosing Results from the 4 week study are expected in the first quarter of 2011, and the 12 week study results are anticipated by the end of 2011. (October 2, 2010)

(Danoprevir)

Genentech announced on August 19, 2009 the initiation of a Phase II clinical trial of RG7227 (ITMN-191) in combination with Pegasys and ribavirin to study safety, tolerability and effectiveness. The study will enroll about 300 patients in 45 global sites. On September 29th it was also announced that a separate study would evaluate the boosting properties of ritonavir when used with the combination of RG7227 (ITMN-191), Pegasys plus ribavirin.

Results from a study of 30 HCV genotype 1 treatment-naive patients treated with ritonavir boosted danoprevir, pegylated interferon/ribavirin for 15 days achieved undetectable viral load of 50% to 100% in the ritonavir boosted danoprevir groups compared to 20% in the placebo group. Treatment of prior non-responders using ritonavir boosted triple therapy is underway. (June 30, 2010)

It was announced on July 31, 2009 that Anadys received FDA clearance to start a phase II study in 90 HCV genotype 1 treatment-naive patients for a dose finding study – First day 800 mg bid followed by 200 or 400 mg, twice daily or placebo in combination with pegylated interferon plus ribavirin for 12 weeks followed by pegylated interferon plus ribavirin for a total treatment duration of 24 or 48 weeks.

A company press release stated that 75% of patients taking a twice-daily dose of 400 mg (plus pegylated interferon/ribavirin were HCV RNA negative after twelve weeks. (October 13, 2010)

(MK-7009)

AASLD 2009: Updated information about the on-going trial (above) was presented. The proportion of subjects who achieved RVR in the MK-7009-containing arms ranged from 69% to 82%, vs. 6% in the placebo group and the percentage of patients who achieved an EVR ranged from 76 to 89% compared to 60% in the placebo group. No serious adverse events resulted in treatment discontinuation. (November 6, 2009)

On March 12, 2009, Vertex announced that it had completed acquisition of Virochem and will be developing Virochem’s HCV polymerase inhibitors in combination with their drug and will study Virochem’s drugs in combination with pegylated interferon plus ribavirin. (March 13, 2009)

PSI-7977 received Fast Track designation from the FDA on August 12. (August 16, 2010)

A study of 48 HCV genotype 1 treatment-naive patients treated with various doses of BMS 790052 in combination with pegylated interferon plus ribavirin for 48 weeks has been completed and data is expected to be released at AASLD(September 30, 2010)

Comments:

Top-line Results—Phase III Studies

SPRINT 2 (1,097 genotype 1 treatment naive patients) response guided triple therapy SVR results of 63% and 66% compared to 38% in the SOC (standard of care) group (without boceprevir).

RESPOND 2 (403 HCV Genotype 1 treatment failure patients) response guided triple therapy SVR 59% and 66% compared to 21% in the SOC group (without boceprevir).

The side effects were similar across all arms of the studies except for anemia which was 20 to 27% higher in the boceprevir groups. However, the discontinuation rate was similar across all arms. More data is expected to be released at AASLD Conference later this year. (August 16, 2010)

Comments: Phase II Clinical Trials:

EASL 2009:

PROVE3 data of 453 patients who did not achieve a sustained virological response (SVR) with a previous course of pegylated interferon plus ribavirin was released. Non-responders by type of non-response were: non-responders (38-39%); relapsers (69-76%); viral breakthroughs (51-52%).

SVR24 results were found to be identical to the SVR12 rates except one person was lost to follow-up.

Study C208 is a new study that is evaluating different doses of telaprevir – 750 mg every 8 hours (q8h or three times a day) compared to 1125 mg dose every 12 hours (q12h or twice a day) in HCV genotype 1 treatment-naive patients. Week 12 data found that 81-85% of patients who received the every 8 hour dose were HCV undetectable compared to 82.1 to 82.5% in the group that received the every 12 hour dose.

EASL 2010: SVR results from Study 107 of people who failed to achieve an SVR with a previous course of pegylated interferon plus ribavirin therapy were released at EASL which found an SVR of 56% in prior non-responders treated for 48 weeks, and 97% and 55% in prior relapsers at 24 and 48 weeks of treatment respectively.

On April 21, 2010 Vertex announced it has begun the marketing application to the FDA for approval of telaprevir and expects to complete the application mid-2010.

Top-line results—Phase III Studies:

ADVANCE: (1,095 HCV genotype 1 treatment-naive patients). SVR was 75% in the group that received telaprevir/pegylated/ribavirin for 12 weeks followed by pegylated/ribavirin for an additional 12 or 36 weeks; and 69% for those who received telaprevir/pegylated/ribavirin for 8 weeks followed by pegylated/ribavirin for 16 or 40 weeks. The control arm (pegylated/ribavirin) which was treated for 48 weeks achieved a 44% SVR. The discontinuation rate due to adverse events was 6.9%, 7.7% and 3.6% respectively.

ILLUMINATE: (540 genotype 1 treatment naive patients). SVR was 72 to 92% based on response--telaprevir, pegylated, ribavirin for no more than 12 weeks and at week 20 were randomized to receive pegylated interferon plus ribavirin (without telaprevir) for an additional period of time that would equal a total treatment duration of 24 or 48 weeks.

Treatment related side effects and discontinuation of therapy was similar in all groups and consistent with side effects seen with pegylated interferon and ribavirin.

REALIZE: Top-line results from Vertex’s phase III study of telaprevir plus pegylated interferon and ribavirin called the REALIZE trial were released today. The trial treated HCV genotype 1 people who DID NOT achieve a sustained virological response (SVR—HCV RNA undetectable 24 weeks after treatment was completed) with a previous course of pegylated interferon plus ribavirin. The study included people who had a relapse (number = 354 patients), who were partial responders (n= 124 patients) or who had a null response (n=184 patients)*.

An overall sustained virological response of 65% was achieved in the telaprevir based arms compared to 17% of people in the control arm (pegylated interferon/ribavirin – without telaprevir). Breaking it down by type of response and when the first dose of telaprevir was given (simultaneous start arm and delayed start arm), the results showed an SVR rate of 83 and 88% in relapsers, 59 and 54% in partial responders and 29 and 33% in null responders. (September 7, 2010)

AASLD 2009: According to a company press release data from a phase one study found that SCY-635 demonstrated promising antiviral activity when combined with HCV polymerase and protease inhibitors. A phase 2 study is expected to begin in the second quarter of 2010. (November 6, 2009)

AASLD 2009: ANA773 demonstrated a substantial antiviral response in HCV patients at 1600 & 2000 mg. Two out of 6 patients in the 1600 mg group and 5 of 8 in the 2000 mg group had a maximal decline > 1 log10. No serious adverse events or early discontinuations were reported. (November 6, 2009)

On May 31, 2010 Can-Fite released top line results which found that in one patient there was a 1.4 log10 decline in HCR RNA (viral load). (June 30, 2010)

On October 7, 2009 Idera announced that patient treatment has been initiated in a phase 1 clinical trial evaluating IMO-2125 in combination with ribavirin in treatment-naive patients with chronic hepatitis C virus (HCV) infection. IMO-2125 is administered subcutaneously once a week for four weeks in combination with daily oral administration of standard doses of ribavirin. Target enrollment is 15 patients per cohort, with 12 randomized to receive IMO-2125 plus ribavirin and three randomized to receive placebo plus ribavirin treatment. The primary objective of the trial is to assess the safety and tolerability of IMO-2125 over an escalating range of dosages in combination with standard doses of ribavirin. The clinical trial is expected to be conducted at five or more sites in France and Russia.

Interim data from the trial above found the drug to be safe and well-tolerated with dose-dependent increases in immune system activation leading to a 40 to 75% (depending on dose) viral load reduction of 1 log10.

On January 19, 2010 Can-Fite announced that it had signed a memo of understanding with Morningside Asia Venture Ltd. to develop CF102 treatment for liver cancer and hepatitis in China, Hong Kong, Macau, and Taiwan. (January 24, 2010)

AASLD 2007: In a study of 24 patients who received bavituximab twice weekly in escalating doses based on body weight for two weeks and where the patients were followed another two weeks, it was found that the HCV RNA viral load reductions were in the moderate range of .5 log10. Bavituximab was found to be generally safe and well-tolerated with no dose limiting toxicities or serious side effects reported. (November 18, 2007)

On January 28th Conatus announced the initiation of a Phase II clinical trial evaluating CTS-1027 in combination with pegylated interferon (Pegasys®) and ribavirin (Copegus®) in refractory HCV patients. Antiviral activity, safety and tolerability of the triple combination will be assessed after up to 48 weeks of therapy. (February 1, 2010)

On January 26, 2009 Debiopharm announced the start of a phase IIb triple therapy study of Debio 025 (60 mg) plus standard doses of Pegasys and ribavirin in 272 HCV treatment-naive genotype 1 patients.

On February 9, 2010, Novartis announced that it had signed an agreement with Debiopharm Group to develop and market Debio 025. (February 15, 2010)

Study results of doses ranging from 5 mg to 400 mg daily (given 1 to 3 times a day) in 105 patients (with various liver conditions) for 14 days reported in Hepatology (August 2007) found that there was a significant reduction of ALT and AST levels in all doses except in the lowest dose group. The study authors concluded that longer studies are needed to assess the potential effects of the drug on liver inflammation and fibrosis. (August 2, 2007)

AASLD 2009: In a study of 25 HCV patients who relapsed to a previous course of treatment and who were given IL-29 and ribavirin (1000-2000 mg) for 4 weeks, it was found that the mean maximum decrease from baseline viral load was 1.8 log10 (0.5-3.6) in the .05 ug/kg group to 3.8 log10 (3.2-5.1) in the 2.25 ug/kg group. In 7 HCV treatment-naive patients who were given 1.5 ug/kg plus ribavirin for 4 weeks it was found that the maximum decrease in viral load from baseline viral load was 3.3 (1.2-5.5)

On October 27, ZymoGenetics announced they had dosed the first patient in a Phase 2 clinical trial of PEG-Interferon lambda (IL-29) and ribavirin in treatment-naive patients with chronic hepatitis C virus (HCV) infection (the “EMERGE” study).

Part B of the phase IIa study (600 pts-genotypes 1 through 4) was initiated using 120, 180 and 240 mcg doses plus ribavirin vs. Pegasys plus ribavirin for a treatment duration of 24 or 48 weeks.

It was announced on September 7, 2010 that Bristol-Myers Squibb acquired ZmyoGenetics. (September 7, 2010)

EASL 2010: The results from 133 patients in the EMPOWER study (formerly 2 studies--Select-2 & 480) found that 31% of the Locteron group were HCV RNA undetectable compared to 19% in the PEG-Intron arm (SOC arm) after 6 weeks of treatment. (April 29, 2010)

EASL 2007: Final results from this study found that 36% of patients who received daily Omega interferon plus ribavirin achieved an SVR compared to 6% who received Omega interferon monotherapy. The company may study higher doses of Omega interferon. (April 17, 2007)

On November 25, 2009 HGS announced that it had submitted an application to the FDA for marketing approval of Zalbin (injection once every 2 weeks & in combination with ribavirin) for the treatment of hepatitis C.

It was announced on June that the FDA had raised some questions about the benefit risk assessment, which means that it is unlikely to have a favorable ruling from the FDA on their application to approve the drug. (June 30, 2010)

Samples from 12 patients (HCV genotype 1) found that the vaccine was safe, immunogenic and had transient effects on HCV viral load. (December 09, 2009)

On December 19, 2007, GlobeImmune announced the initiation of a phase II study expected to enroll 120 patients who will receive Tarmogen in combination with pegylated interferon plus ribavirin and compare the triple to regular standard of care (pegylated interferon with ribavirin).

AASLD 2009: Report from an ongoing Phase 2b study to compare GI-5005 plus pegylated interferon plus ribavirin versus pegylated interferon/ribavirin alone in 140 HCV genotype 1 patients who were either treatment-naive or prior non-responders. On a modified intent-to-treat basis (patients having received at least one dose of combination therapy), treatment-naive patients receiving GI-5005 plus pegylated interferon/ribavirin as a triple therapy had an end-of-treatment complete response rate (HCV RNA < 25 IU/mL by PCR assay at 48 weeks) of 74%, compared with an end-of-treatment response rate of 59% for treatment-naive patients receiving pegylated interferon/ribavirin (without GI-5005). (November 6, 2009)

IC41 has completed Phase I & Phase II studies and has been shown to have a good safety profile in healthy adults and previously treated HCV patients who failed to achieve a successful treatment outcome. In the HCV patients there was an increase in T-cell response and a temporary reduction of HCV RNA (viral load).

AASLD 2009: Final results: The use of IC41 did not conclusively find a viral load reduction except in the group with a high viral load. (November 13, 2009)

Doxorubicin Transdrug®, a treatment presented in the form of nanoparticles delivered via hepatic intra-arterial route, was granted orphan drug status in Europe and the United States. It is being evaluated in patients with advanced hepatocellular carcinoma.

Phase II results showed a 88.9% survival rate after 18 months of treatment in patients having received three intra-arterial doxorubicin Transdrug® injections, as per protocol. This increased survival rate is relevant compared to the 54.5% rate observed in patients with the current standard of care (usually transarterial chemoembolisation with a cytotoxic drug).

Based on these data, BioAlliance Pharma will design new approaches using doxorubicin Transdrug® while reducing pulmonary adverse events that led to the suspension of the trial. (December 10, 2009)

FDA Approved

On December 3, 2009 Celsion reported that enrollment in this 600 patient study continues to accelerate and Celsion expects to meet its objective of completing enrollment by the middle of 2010. A pre-planned, un-blinded interim efficacy analysis will be performed by an independent Data Management Committee when 50% of the endpoint events, tumor recurrence, are realized in the study population. Based on an historical review of RFA cases, Celsion expects the study could be completed by the middle of 2011, and pending positive data, a NDA would be submitted to the FDA before the end of 2011.

On February 11, Celsion announced that the Data Monitoring Committee (DMC) had reviewed the safety data and has recommended that the study continue. (February 15, 2010)

On June 1, 2009, Bayer and Onyx announced the initiation of a trial to study the combination of Nexavar and Tarceva (Genentech) in patients with liver cancer. The trial is expected to enroll 700 patients with advanced liver cancer to find out if the combination prolongs survival time. (July 1, 2009)

In April 2008, Ligand initiated a Phase IIa trial evaluating LGD-4665 in ITP patients in a randomized double-blind, placebo-controlled, proof of concept study. (December 8, 2008)