Trials begin on hepatitis C drug

The first human clinical trials have started on a new drug developed to treat infections caused by the hepatitis C virus.

The medication, taken orally, was first prepared at the Welsh School of Pharmacy at Cardiff University in 2008.

Laboratory tests showed it killed 90% of the virus at very low concentration.

Trials in healthy volunteers to assess the drug's safety are being held before its effectiveness on patients is tested in trials next year.

Approximately 170m people around the world are affected by hepatitis C, which can lead to liver cancer and cirrhosis and can be fatal.

It is the leading cause of liver transplantation in western countries.

The current treatment involves two drugs - ribavirin and interferon, which has to be given as an injection.

Side effects are often severe and lead to patients failing to complete the treatment.

However, researchers at the university believe the new drug, INX-189, is one of the most potent of its kind developed to date.

US pharmaceutical company Inhibitex, which owns the licence to INX-189 and has been working with the Cardiff team, is running the trials.

'Encouraging progress'

Professor Chris McGuigan, of the Welsh School of Pharmacy, who is the academic lead on the project, said the trials were in a "a very early stage".

"However, progress has been encouraging so far, going from the laboratory to human trials within 18 months.

"We believe that INX-189 offers the possibility of more potency against hepatitis, more rapid action in the liver, and fewer side effects than existing treatments."

Cardiff University and Inhibitex filed a patent on INX-189 earlier this year. It has been cleared for human clinical trials by the Food and Drug Administration in the US.

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Additional Data From Phase 1b Study Of Hepatitis Drug Shows Positive Results

Biopharmaceutical company Achillion Pharmaceuticals Inc. said Tuesday that an additional preliminary data from its Phase 1b clinical trial of HCV Protease Inhibitor demonstrated positive results, with meaningful reductions in Hepatitis observed, and accompanied by continued safety and tolerability levels. Following the disclosure, the company's share were up 17.37% in the after hours trade.

Hepatitis C virus is the most common cause of viral hepatitis, an inflammation of the liver, and is currently estimated that more than 170 million people are infected with HCV worldwide.

ACH-1625 is an inhibitor of HCV NS3 protease that was discovered, and is being developed by Achillion. In preclinical studies, ACH-1625 demonstrated high potency, unique pharmacokinetic properties and an excellent safety profile at high drug exposures.

Now with the Phase 1b study, Achillon said the additional data revealed that both the third and fourth patient cohorts receiving treatment with ACH-1625 achieved meaningful reductions in HCV RNA after a five-day monotherapy.

Achillon said that results from its Third Dosing Cohort with 9 subjects, administered 200 mg twice daily over a 5 day period, showed a mean maximum reduction in viral load of 3.86 log10, compared with a mean rise of 0.16 log10 in the placebo group. Also, all subjects in the treatment group had a viral load decline greater than than 3.0 log10, and that there were no serious adverse events, and no clinically significant changes in vital signs, or laboratory evaluations. All adverse events in patients receiving ACH-1625 were classified as mild or moderate and were transient, with sustained viral suppression observed, the company added.

Further, the company said that the Fourth Dosing Cohort, with 8 subjects on a 600mg once daily dosage for five days, showed a mean maximum reduction in viral load of 3.81 log10 was achieved in the treatment group, compared with a mean rise of 0.24 log10 in the placebo group. Achillon stated that, all subjects in the treatment group had viral load decline greater than 3.0 log10, and that safety results were similar to those observed in previous segments of the trial. However, Achillon added, there was one non-drug-related serious adverse event, a bone fracture in a patient receiving placebo, but there were no clinically significant changes in vital signs, or laboratory evaluations. All reported adverse events in patients receiving ACH-1625 were classified as mild or moderate and were transient, with sustained viral supression observed.

Chief Executive Officer Michael Kishbauch said " It is impressive that at all dose levels ACH-1625 has shown meaningful viral load reduction and sustained viral suppression post treatment course. Importantly, we believe the results from these last two cohorts demonstrated that ACH-1625 was effective at a lower dosing level and in a once-daily dose, features that distinguish our drug and suggest it could offer improvements over other protease inhibitors currently in development.

If the results are sustained through further development, then ACH-1625 would contend as a potential best-in-class protease inhibitor, Kishbauch added.

Earlier, in Phase 1a safety studies with ACH-1625, where subjects were exposed to both single ascending dose, and multiple ascending dose, preliminary data demonstrated ACH-1625 was well tolerated at all doses and there were no serious adverse events, and no clinically significant changes in vital signs, and adverse events were classified as mild or moderate.

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Santaris Plans Phase II Trial of miRNA-Targeting HCV Drug

Santaris Pharma is close to completing a second phase I study of its microRNA-targeting hepatitis C therapy SPC 3649, and expects to move the drug into phase II development later this year, a company official told RNAi News.

The official, CSO Henrik Orum, also said Santaris has dropped its near-term plan to seek a partner for the therapy, which it will instead carry on its own at least through the first phase II trial in HCV-infected patients

SPC3649 targets miR-122, the most abundantly expressed miRNA in the liver and one linked to cholesterol regulation and lipid metabolism. It is based on Santaris' locked nucleic acid technology, which comprises nucleic acid analogs in which the ribose ring is locked by a methylene bridge connecting the 2'-O atom with the 4'-O atom.

In mid-2008, Santaris moved the drug into a phase I study, making it the first to test a miRNA-targeting drug in man. According to Orum, that single ascending dose trial enrolled 64 healthy volunteers and initially examined doses of the drug up to 6.4 mg/kg.

"With the initial top dose of 6.4 [mg/kg], we didn't see anything in terms of the safety issues," he said. As such, the company amended the trial to include 9 and 12 mg/kg doses.

In addition to observing no significant adverse events associated with SPC3649, Santaris saw evidence of a pharmacological effect as measured by reductions in serum cholesterol — a biomarker for miR-122, Orum explained this week during a presentation at the IBC Life Sciences' Oligonucleotide Therapeutics Discovery conference held here.

The company also initiated a second phase I study, this time examining multiple ascending doses of the drug, which it expects to wrap up shortly, he said.

Because data from this trial have not been publicly disclosed, Orum declined to comment on them. He did say, however, that Santaris is "happy with the results" and that the company is slated to begin a phase II study in HCV-infected patients "later this year."

Both phase I studies were conducted in Denmark. He noted that the company is considering in which countries it will run the phase II trial.

Meanwhile, Santaris has made the decision to keep SPC3649 in-house after partner GlaxoSmithKline opted against licensing the drug.

In late 2007, the companies inked a deal to develop and commercialize antiviral drugs based on the LNA technology (RNAi News 12/20/2007). As part of that arrangement, GlaxoSmithKline had the option to in-license SPC3649.

But as reported by RNAi News, GlaxoSmithKline let that option expire (RNAi News 12/3/2009), leaving Santaris free to host licensing negotiations with other interested parties.

Notably, GlaxoSmithKline later said it had partnered with rival miRNA drug firm Regulus Therapeutics on a miR-122-targeting drug for indications including HCV (RNAi News 2/25/2010).

This week, however, Orum said that despite "considerable interest … [in SPC3649] we've elected to keep it as a Santaris asset until we have conducted the first trials in patients with HCV. We think there is significant value creation in that phase, and we'd obviously like to retain that within Santaris … we have patient data."

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Vertex hepatitis C drug telaprevir works well in twice daily dosing

Vertex Pharmaceuticals Inc's closely watched hepatitis C drug telaprevir proved nearly equally effective in a twice daily regimen as three times a day, knocking out the virus in more than 80 percent of patients in both groups in a small study.

All previous Phase II studies of the highly promising experimental drug tested the medicine at three times a day dosing given at eight-hour intervals. This study hoped to show telaprevir could be administered twice a day 12 hours apart, which would be more convenient for patients.

Patients who received telaprevir twice a day in combination with the standard treatments of pegylated-interferon and ribavirin had a sustained viral response (SVR) of 82 percent in one arm and 83 percent in another, depending on which brand of interferon they received.

That compared with 81 percent and 85 percent of patients who were given telaprevir in the three times daily regimen, according to data to be presented at the American Association for the Study of Liver Diseases (AASLD) meeting in Boston.

The percentage of patients in whom the virus is undetectable 24 weeks after completing treatment yields the critical measure known as sustained viral response, or SVR, which is considered tantamount to a cure.

"SVR rates of 75 to 80 percent (in twice daily dosing) would be very well received by investors," Sanford Bernstein analyst Geoffrey Porges said prior to release of the data.

"I was expecting around 70 percent," Dr Patrick Marcellin, the study's lead investigator, said in an interview.

"This is the highest we have observed with this triple therapy and the major conclusion is that the rate of SVR is similar in those patients who received bid (twice daily) and those who received it three times daily," said Marcellin, a professor of medicine at the University of Paris and head of Viral Hepatitis Research Center in Hospital Beaujon.

Importantly, Marcellin noted, even though the telaprevir dose was higher in the twice daily regimen, there were "no new side effects, and that is very encouraging."

Investors may also be encouraged by the low 3 percent dropout rate due to serious rash, which had been a source of some concern in earlier studies. Just four of 161 patients discontinued treatment due to rash, with another three pulling out due to anemia.

Marcellin said doctors have learned how to manage the rash and are now less likely to discontinue treatment as a result.

The open label study tested treatment naive patients, or those who had not received prior treatment for the serious liver disease. Treatment duration depended on how quickly patients responded to the medicines, an approach known as response-guided therapy.

Patients who achieved rapid viral response, defined as undetectable levels of virus at week four, and who maintained undetectable levels through week 20, were able to stop all treatment after 24 weeks of therapy -- 12 weeks on the three- drug combination and 12 more of standard therapy.

They were then followed for six months post treatment to determine whether they achieved SVR.

Eighteen percent of patients in the study did not meet that rapid response criteria and received a total of 48 weeks of treatment with the standard drugs.

Three percent of patients in the study relapsed during post-treatment follow-up, the company said.

"This study confirms that 24 weeks can be used in the large majority of patients with with high efficacy. Shorter duration means less side effects and better quality of life," Marcellin said, noting that "tailoring treatments according to the very early response improves the management of the patient and the chance of the patient to be cured."

There has been high hope that telaprevir will allow for 24 weeks of treatment for many patients. The current drugs must be taken for 48 weeks and are often difficult to tolerate, with many patients suffering flu-like symptoms for the duration.

"Many of these patients are relatively young and very active, so to treat shorter is a real benefit," Marcellin said.

He cautioned that this was a small study and that much larger Phase III clinical trials must confirm the results.

But he added: "As a clinician for our patients, this is an important hope for the future. This is a big step in the history of the treatment hepatitis C."

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Drug shows promise against hepatitis C

An experimental drug greatly increased the number of people who appear to be cured of hepatitis C infection, according to results of mid-stage testing. The findings also suggest the drug telaprevir, made by Vertex Pharmaceuticals Inc., which sponsored the two studies, can cut treatment time from one year to six months. However, those taking the drug reported more side effects including severe rash, nausea and anemia than those on standard treatment alone.

Still, telaprevir and similar drugs that other companies are testing offer hope of a major advance against the disease, which afflicts about 3.2 million Americans and 180 million people worldwide. It is caused by a bloodborne virus that can lead to liver scarring or liver cancer.

Treatment is aimed at helping the immune system eliminate the virus. Current therapy combines the drugs peginterferon and ribavirin, but less than half on it are cured. Telaprevir and similar drugs under development are a potential game-changer because they specifically attack the hepatitis C virus.

In the two studies, roughly two-thirds given telaprevir with standard therapy for six months showed no signs of the virus after six months, which doctors considered being cured of the disease. That's compared to 40 to 50 percent on standard treatment alone.

We can now sit down with our patients and tell them that 2 of 3 patients can be cured with a 24-week course of therapy, said Dr. John McHutchison, a Duke University doctor who led one study and has consulted for Vertex, based in Cambridge, Mass.

Telaprevir is in late-stage testing and is not available commercially; the company plans to seek government approval next year.

Results were published in Thursday's New England Journal of Medicine.

Hepatitis C is a huge and growing problem because for years there was no way to screen the blood supply for the virus. Infection often doesn't produce symptoms for many years, so many of these cases are just now being recognized even though they may stem from transfusions a decade or more ago.

The virus is mainly spread through contact with the blood of an infected person. It can be contracted by sharing dirty drug needles, getting pricked with a hospital needle with infected blood or being born to an infected mother.

About a quarter of people exposed to hepatitis C clear it out of their bodies without treatment. But the rest develop a lifelong infection that attacks their livers. There is no vaccine against hepatitis C.

In one study of 250 people with chronic hepatitis C in the United States, 61 percent who took telaprevir with standard therapy for six months cleared the virus, compared with 41 percent on standard therapy alone. Among those who took the drug and standard therapy for a year, 67 percent had no signs of infection.

However, twice as many on telaprevir stopped treatment because of side effects.
In another study of 334 people in Europe, 69 percent on telaprevir and standard therapy for six months had undetectable virus levels compared with 46 percent on standard treatment alone.
The European study was led by Dr. Christophe Hezode of Henri Mondor Hospital in France.

Hezode has consulted for Swiss drug maker Roche, which makes peginterferon and ribavirin.

Testing of even shorter treatment times did not show benefit in either study.

Telaprevir appears to be a material advance in the therapy of hepatitis C, beginning a new era of treatment, Dr. Jay H. Hoofnagle of the National Institute of Diabetes and Digestive and Kidney Diseases wrote in an accompanying editorial.

Other doctors were more cautious.

The new drug does show promise. However, its side effects remain a concern, said Dr. James Ou, a hepatitis expert at the University of Southern California's Keck School of Medicine.Other companies developing similar drugs include Idenix Pharmaceuticals, Schering-Plough Corp. and InterMune Inc.

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Regulator approves new drug for chronic Hepatitis B patients

HI-EISAI PHARMACEUTICAL Inc., a subsidiary in the Philippines of Eisai Co., Ltd., recently announced that the Bureau of Food and Drugs (BFAD) approved Clevudine as a Nucleoside Reverse Transcriptase Inhibitor.

It is indicated for the inhibition of virus replication in chronic hepatitis B patients (HBeAg positive or HBeAg negative) with evidence of active viral replication and elevations in serum aminotransferases (ALT or AST).

Clevudine is an antiviral drug with an inhibitory effect on DNA polymerase for the treatment of chronic Hepatitis B. In the Philippines, about eight million people are believed to be infected with Hepatitis B.

With its potent and sustained anti-viral effect, Clevudine is expected to be a new treatment option for patients with deterioration in liver function caused by Hepatitis B.

Clevudine will be available in the country soon. Meanwhile, B patients are advised to seek medical consultation from health care professionals.

Dr. Jose Sollano, president of the Hepatology Society of the Philippines, said that the introduction of new compounds effective against the Hepatitis B virus strengthens our resolve to pursue relentlessly the treatment of chronic Hepatitis B.

It also gives the patients good reason to commit to the therapy immediately, in as much as the desired outcomes of treatment are now attainable.

This development complements well for the doctors’ desire at tailor-fitting certain drug treatments to individual patients in order to ensure a successful outcome of their chosen treatment against chronic hepatitis B.

Eisai obtained exclusive right to develop, manufacture and market Clevudine in eight Asian countries including China from Bukwang Pharma, a South Korean pharmaceutical company, and has been developing Clevudine in those countries.

The Philippines is the first country among them to get approval of Clevudine for marketing. Eisai is currently proceeding with the preparations for filing for approval of Clevudine in the remainder of the countries.

Eisai develops and markets drugs for liver diseases that include Stronger Neo-Minophagen C_, Glycyron_ and Livact_ in China and other Asian countries.

Source : www.bworldonline.com

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