With lead hepatitis C virus (HCV) candidate simeprevir (TMC435) nearing the finish line and two nucleotide (nuc) polymerase inhibitor candidates for HCV in its pipeline, Medivir AB pulled the plug on its NS5A inhibitor program, citing lack of market demand, difficulty meeting its development timetable and the desire to reallocate in-house resources.

The Stockholm-based company said it will focus future HCV R&D efforts exclusively on its nuc programs – one already partnered with Janssen Pharmaceuticals, a unit of Johnson & Johnson, of New Brunswick, N.J., which also holds global rights to simeprevir outside the Nordic region.

Medivir had disclosed a single NS5A replication complex inhibitor that was in preclinical optimization, designed to expand potential interferon-free combination options in HCV, but company spokesman Rein Piir said the program actually encompassed "many different molecules." Medivir struggled to reach development goals on an internally established timetable, he acknowledged.

"A lot of companies claim that they have a true next-generation NS5A," Piir told BioWorld Today. "So far, we haven't seen that."

Although Medivir's scientists saw slight improvements over first-generation NS5A inhibitors during early stage research, the differentiation was not sufficient to justify continued investment in the program, he explained. At the same time, progress in Medivir's nuc programs encouraged the company to accelerate their development.

Despite outstanding Phase III data on NS3/4A protease inhibitor simeprevir, Medivir and J&J have been criticized for lagging some rivals in progressing oral, interferon-free HCV regimens. Piir acknowledged the competitive landscape includes many nuc candidates in the clinic and late stage preclinical development – "maybe even too many," he suggested. (See BioWorld Today, Dec. 21 , 2012.)

In April, Janssen submitted a new drug application for simeprevir, which was granted priority review by the FDA for once-daily administration with pegylated interferon and ribavirin for the treatment of genotype 1 chronic HCV. The company also filed a marketing authorization application for the compound with the European Medicines Agency.

Most of the resources devoted to the NS5A project now will help the company's nuc programs potentially to leapfrog competitors. Piir declined to discuss how much funding or staff would be redeployed, but said, "if you want to have a program, you need to have at least 20 people or so." The company does not plan to reduce head count in its research discovery programs, which account for some 75 staff, he added.

"If we had reached or at least could say within a quarter or so we could reach the [NS5A] target profile, in that case we would probably advance both in parallel," Piir added. Instead, Medivir decided that advancing multiple nuc programs represented an easier path toward investigational new drug (IND) candidates and potentially higher payback.

Focusing resources on nucs, which have emerged in recent years as the darlings of HCV development, also is more likely to attract a suitor for the second Medivir program, according to Piir.

Although "it's too early to say" whether the company might seek to advance the second nuc toward pivotal trials before seeking a partner, "there is much higher interest for nucleotides," he said, "and we have a clearer view of what's needed" to characterize the molecules.

"First, we need to get that program to the point where we can reflect" on the partnering question, Piir added. "We know what kinds of companies are interested in what kinds of programs."

Nuc Development No Done Deal

Gilead Sciences Inc., of Foster City, Calif., could be first to market with an interferon-free, all-oral regimen. The company expects the FDA's decision on sofosbuvir (formerly GS-7977) on Dec. 8. (See BioWorld Today, Nov. 13, 2012, and Feb. 6, 2013.)

However, nuc technology is not without its pitfalls. In July, the FDA imposed a partial clinical hold on an ongoing Phase II study of the nucleotide analogue polymerase inhibitor, VX-135, from Cambridge, Mass.-based Vertex Pharmaceuticals Inc. due to observations of elevated liver enzymes in patients receiving a 400-mg dose in the trial. The hold stopped evaluation of the 200-mg dose, but assessment of the 100-mg dose of VX-135 in combination with ribavirin continues as planned. (See BioWorld Today, July 29, 2013.)

And in June, Idenix Pharmaceuticals Inc., also of Cambridge, Mass., suffered another in a series of blows to the development of its HCV pipeline when the FDA requested additional preclinical safety data for IDX20963, its lead uridine nucleotide prodrug, resulting in a delay in initiating its U.S. clinical trials. (See BioWorld Today, June 24, 2013.)

Earlier, Idenix discontinued clinical development of IDX184, a nuc in Phase IIb testing, and IDX19368 ('368), another nuc for which the company had filed an IND but had not initiated dosing. The FDA placed IDX184 on a partial clinical hold and '368 on clinical hold in August 2012 following a patient death and nine hospitalizations during the Phase II trial of another nuc, BMS-986094, by New York-based Bristol-Myers Squibb Co. Its development also was subsequently halted. (See BioWorld Today, Aug. 3, 2012, Aug. 17, 2012, and Aug. 27, 2012.)

Medivir has a realistic take on the challenges.

"Speed to market is one thing," Piir said, "but when it comes to nucleotides, safety and efficacy are not that easy to get together. We have seen different failures with some of these compounds in the last year.

"But now we are focused on one thing," he added. "And we have [experience] from our lead compound that hopefully will bring something to the table."

Shares of Medivir (STOCKHOLM:MVIRB) seesawed on Thursday before ending the day at SEK73 (US$11.21) for a gain of less than 1 percent.