Competition may threaten Gilead as market leader

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A few years after hep. C became the infectious-disease headliner, the show's credits are still running. At the same time, companies in the space have (finally) shifted their focus to solving the superbug dilemma. The lifesaving aspects of anti­biotics often go overlooked, but the effects will be devastating if these infection-erasing solutions begin to slip out of reach.

The bacteria crisis spurred a new style of collaboration for public and private entities, regulatory bodies, and governments. The mission? Replenishing the diminishing antibiotics pipeline while solving scientific and financial challenges.

See also: Drugmakers renew interest in antibiotic development

“I haven't seen this much collaboration since the early days of HIV,” says Dr. Joan Drucker, VP and head, infectious diseases and vaccines center of excellence, Quintiles.

Even as R&D investments begin to climb, some experts are concerned about the lack of prospects for drugs attempting to counteract the commonest bacterial infections. A few new intravenous agents gained approval for hospital use, but their application is limited.

“For the most common bacterial infections — those occurring in the outpatient setting — there's been little to discuss,” explains Peter Villucci, Cadient's executive creative director.

The industry needs to keep a standing army and cannot rely on drafting people (or more specifically, their know-how) when an issue pops up, explains Michael Dudley, SVP and head, R&D and co-leader of the infectious disease global innovation group at The Medicines Co.

“To be better prepared, we need to pull innovative companies into the field and enforce more public–private relationships to carry it over,” Dudley proposes.


"The old model, in effect since penicillin's discovery, has been effective. But the future will bring agents that target specific bacteria and mutations without affecting other bacteria in the microbiome."

Neal Dunn, partner at Trinity Partners


 

A new drug class hasn't arrived on the scene in some time. Indeed, most “new” candidates are tweaks of existing antimicrobials, not dramatic improvements. Companies like Merck, Allergan, and Achaogen walk more traditional pathways to combat highly drug-resistant pathogens, while others delve into new areas.

“The old model, in effect since penicillin's discovery, has been effective,” says Neal Dunn, a partner at Trinity Partners. “But the future will bring agents that target specific bacteria and mutations without affecting other bacteria in the microbiome.”

Drucker lauds Merck's recent scientific breakthrough in Clostridium difficile. Acquired in the Cubist Pharmaceuticals buy-out, bezlotoxumab is a monoclonal antibody (mAb) that blocks a toxin damaging the gut wall and causing inflammation without disrupting other bacteria. “If it succeeds, there will be a large-scale change in how we think about antibiotics,” she says.

THE MONOCLONAL ANTIBODY APPROACH

Spero Therapeutics is stepping out with a potentiator approach, and companies like MedImmune are betting on mAbs. The mAb approach is in its infancy, but it speaks to the infectious diseases space's interest in joining other therapeutic categories in embracing precision medicine.

The ID biologics of tomorrow will boast excellent safety profiles and generate a highly pathogen-specific approach without the collateral damage to the microbiome associated with broad-spectrum antibiotics. MedImmune's antibacterial portfolio centers on an anti-toxin mAb to prevent nosocomial pneumonia caused by Staphylococcus aureus and a novel bispecific mAb to prevent nosocomial pneumonia caused by highly drug-resistant P. aeruginosa. XBiotech's mAb 514G3 advanced to Phase II trials for the treatment of all forms of S. aureus infections, including Methicillin-resistant S. aureus (MRSA).

See also: Top 25 infectious disease products in 2015

Spero is developing derivatives of the potent yet highly toxic polymyxin class to give other drugs a boost in penetrating gram-negative bacteria. The goal is to revitalize ineffective or inactive antibiotics by pairing them with a potentiator.

Pursuing drug development avenues combined with other antibiotics is uncon­ventional. “Combining drugs to combat bacteria is one of the best approaches we have right now,” says Dr. David Nicholson, head of brand R&D at Allergan.

PHARMA'S EXIT AND RE-ENTRY


Responsible for the lion's share of approved or investigational antibacterial agents, biotech companies have made a splash in the sector. “The entrepreneurial DNA of small biotechs will continue to drive R&D in underexplored therapeutic areas,” Villucci notes. So where has pharma been? Bernie Zeiher, president of development at Astellas, attributes the industry's scaled-back R&D efforts to a handful of factors. Among them: the expense, limitation, and size of clinical trials, historically stringent regulatory oversight, and unattractive commercial returns. Nevertheless, big pharma investments are beginning to trickle in.

“With the WHO and the CDC spreading the word about antibiotic resistance, pharma is recognizing the huge health and business opportunities,” Villucci says.

Companies like AstraZeneca, Glaxo­Smith­Kline, Janssen, Merck, and Roche not only stuck around during lean times but are now also spearheading pipeline efforts in the space. And government incentives are putting an attractive sheen on the space and easing drug manufacturers' woes in bringing new anti­microbials to market.

Unsurprisingly, commercialization is the big chal­lenge. “These drugs don't require chronic administration, bringing the commercial return into question,” Nicholson notes. “How much can you charge for a lifesaving acute treatment? It's a debate in the industry.”

Eighty pharma, biotech, and diagnostic firms signed on the dotted line of an industry declaration to collaborate with governments to mitigate the financial risks involved in the R&D of new antibiotics.

Achaogen COO Blake Wise characterizes the industry declaration as a commitment to awareness, aiming to bring more players into the fold. “We hope the public will understand that biopharma is on the healthcare ecosystem's side in attacking the problem,” he says.

For its part, the FDA has indicated an increased flexibility and willingness to speak with sponsors about alternate development pathways. Designations including Qualified Infectious Disease Product, enacted under the GAIN Act, have ushered in drugs like Dalvance, Orbactiv, and Sivextro, awarding developers an expedited FDA application review and five years of additional marketing exclusivity.

The FDA has also moved to approve antibacterials on the basis of Phase II data. A prime example is Allergan's Avycaz, codeveloped with AstraZeneca, which gained U.S. approval last year for intra-abdominal infections following the release of Phase II data.

“It's the FDA living up to its word. The agency said it'd make these agents easy to approve and it did,” Nicholson says. “We'll continue the dialogue to see what's next, but it's certainly a step in the right direction.”

The speedier market path has drawbacks. Allergan, for example, is pursuing Phase III studies to expand Avycaz's somewhat-restricted approved label. Companies must also continue to contend with pricing and reimbursement issues.

On the other hand, the NIH, BARDA, and others are pumping money into the sector to pick up the tab for some of the development costs, plus the number of global collaborative partnerships has skyrocketed. “We realize we're smarter collectively and that much of the discovery comes from scientists sharing basic knowledge with one another,” Drucker says.

DIALING IN DIAGNOSTICS

It's not all about ­stockpiling treatment options when warding off drug-resistant pathogens. Both early diagnosis and complete prevention of infections need to be considered as part of the plan of attack.
The industry declaration thus zeroed in on the enhanced use of diagnostic tests to rapidly identify infecting organisms and guide more appropriate clinical treatment decisions.

Drucker believes science is ripe for more advanced diagnostics. “Treatment paradigms moved toward a broader approach about 10 years ago to be sure we didn't miss a pathogen,” she says. “Now the pendulum is swinging the other way and we need to get more specific with the treatments we give.”

With faster diagnostics, clinicians will find themselves in a better position to target bacteria. “We can pick a narrower antibiotic pathway because we know the target,” Drucker continues. “That will help us pull away from the broad-spectrum approach and minimize the resistance piece.”

Not so fast, says Dudley. He agrees that diagnostic technology is highly promising in the infectious diseases sector but notes that these tests need to be available immediately. He also points to education's role in the adoption of new tests. “Stewardship practitioners can stand in the gap and translate the information these tests produce,” he explains.

HEPATITIS HYPE


During the past few years the market has been wowed by a new crop of wildly successful hep.-C medications. Sales of Gilead's Harvoni (ledipasvir/sofosbuvir) grew meteorically in 2015, but grumblings of flattening sales have infiltrated the financial community. Along with competition from Merck's Zepatier (elbasvir and grazoprevir), approved to treat hep.-C genotypes 1 and 4 adult patients, Harvoni's position could be threatened.

Merck's move to sell its once-daily oral treatment at a meaningfully reduced price point (compared to Harvoni, anyway) is seen as a purely strategic move within a segment dealing with payer and access issues. Gilead's soon-to-be-launched fixed-dose combination of Sovaldi (sofosbuvir) and investigational pangenotypic NS5a inhibitor velpatasvir could make up for sliding sales.

In hepatitis B, ContraVir Pharmaceuticals is comparing CMX157 to Gilead's Viread (tenofovir disoproxil fumarate) in a Phase IIa trial. CMX157 is a highly potent lipid conjugate of tenofovir, the active molecule in market leader Viread.

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