Editor

Editor's note: This is a special reprint from the June 27, 2011, edition of BioWorld Insight.

Science has taught us that many diseases – including HIV, HCV and cancer – can only be controlled by cocktails containing several drugs. Business has taught us that the best drugs don't necessarily come from your own pipeline, and they aren't always for sale. Hence the rise of no-money, no-rights, no-strings-attached deals to combine multiple unapproved drugs from multiple sponsors in a single clinical trial.

In years gone by, this business development model was "not the natural inclination of pharma or biotech," said Jeremy Levin, senior vice president of the strategic transactions group at Bristol-Myers Squibb Co. But what BMS terms the "clinical collaboration agreement," or CCA, is becoming an important "arrow in the quiver" for licensing execs, Levin said.

In the HCV space, Pharmasset Inc. and BMS recently started a Phase IIa trial that combines Pharmasset's nucleotide polymerase inhibitor PSI-7977 with BMS's NS5A inhibitor BMS-790052. Meanwhile, Anadys Pharmaceuticals Inc. is testing its non-nucleotide polymerase inhibitor setrobuvir (ANA598) with an undisclosed company's investigational antiviral.

Similar deals are cropping up in the cancer space. BMS recently announced plans for a melanoma trial combining CTLA-4 inhibitor Yervoy (ipilimumab) with BRAF inhibitor vemurafenib, from Roche and Daiichi Sankyo Group subsidiary Plexxikon Inc. Although Yervoy is approved, the deal was in the works before the FDA blessed the drug. (See BioWorld Today, June 7, 2011.)

Conducting a clinical trial that combines an investigational drug with an approved drug isn't new: Investigational cancer drugs are often combined with approved chemotherapies during clinical trials, and investigational antivirals are often layered on top of the standard of care.

But combining two investigational drugs is much more scientifically complex, from figuring out the dosing to managing any safety signals. Combining two investigational drugs from two different companies adds a layer of business complexity, raising questions such as who will hold the investigational new drug (IND) application, who will take the lead on trial design and who will foot the bill.

"It's risky for both parties," said Sara Sandifer, analyst with Deloitte Recap LLC. Yet CCAs are definitely on the rise, indicating the risk comes with some significant rewards.

Science is the Driving Force

The original poster child indication for collaborations between drug companies was HIV. In order to help patients manage complex regimens of 15 to 20 pills that had to be taken at various times throughout the day and with various food requirements, BMS and Gilead Sciences Inc. teamed up to create once-daily Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate). (See BioWorld Today, Dec. 21, 2004.)

But the components of Atripla were already FDA-approved and combined widely in clinical practice when BMS and Gilead formed their joint venture. In cancer and HCV, disease biology rather than convenience is the driving force, and companies are taking the lead by combining unapproved drugs rather than waiting for doctors to experiment with combinations of approved drugs.

In HCV, data indicate combinations of direct-acting antivirals (DAAs) might achieve high cure rates, if viral breakthroughs can be controlled. In a Phase II trial of protease inhibitor BMS-650032 and NS5A inhibitor BMS-790052, six of 11 patients broke through, but the others achieved a cure. Thus it was "very logical" for BMS to seek to combine its NS5A inhibitor with Pharmasset's nucleotide polymerase inhibitor PSI-7977, which protects against viral breakthroughs, said Richard Smith, Pharmasset's vice president of investor relations and corporate communications.

Smith noted that nucleotides are the backbone of HIV, HBV and herpes drug cocktails, and "we think they will be the backbone in HCV." Pharmasset wants to prove it can combine its drugs "with any class of drugs out there" – but since it doesn't have an NS5A inhibitor in its internal pipeline, teaming up with BMS was logical for the biotech as well.

In cancer, too, it is becoming increasingly clear that cocktails of drugs will be required to manage resistance mutations. At the American Society of Clinical Oncology annual meeting earlier this year, Yervoy investigator Jedd Wolchok said vemurafenib has spectacular, but seldom durable results, while Yervoy has a lower response rate, but relatively high rate of long-term success. The two drugs "complement each other nicely," he noted.

Plexxikon President Kathleen Glaub said clinical investigators were "clamoring for a combination of vemurafenib and some immunotherapy" – such as Yervoy – because vemurafenib's mechanism of action is thought to release antigen and prime the immune system. Thus when BMS approached Plexxikon and partner Roche about a combination trial, the seeds of scientific rationale had already been sown.

No Money? No Rights? No Problem.

But why not just license rights to the drug you want to combine with your own, or acquire the other drugmaker outright?

After all, when Vertex Pharmaceuticals Inc. wanted other antivirals to combine with its HCV drug Incivek (telaprevir), it paid $377 million to acquire ViroChem Pharma Inc. and then licensed additional products from Alios BioPharma Inc. in a $1.5 billion deal. (See BioWorld Today, March 5, 2009, and June 14, 2011.)

BMS' Levin explained that a license means you want to develop that drug, you want to share the rights, you feel confident that you have the best possible combination. But in cancer and HCV, where the biology is still evolving and the drugs are still experimental, no one knows what the best combinations will be. It's best to see where the science leads, and "you don't have to own something" to explore that, Levin said.

Glaub added that "industry is getting more pragmatic. Over the past 10 years, there has been a greater recognition that not all good ideas come from your own R&D." That realization has driven a huge increase in licensing and acquisitions, and CCAs are "just another aspect of that," she said.

The stage of the companies involved is also a major factor. For a preclinical company like Alios, signing a partnership with Vertex brought in needed cash and removed a lot of risk. But for Pharmasset, which is well into Phase II studies and well financed, Smith said "why would we give up the rights?"

Meanwhile Plexxikon had already partnered vemurafenib with Roche, which is not exactly an easy acquisition target.

"There are many different ways of collaborating," Levin told BioWorld Insight. "We've learned . . . you must focus on finding the best modality and craft the right kind of agreement. You can have an acquisition or a license or a CCA. We don't walk in a priori with a concept, we are guided by what is the fastest way of doing things and . . . what delivers the most value to patients."

Sandifer predicted the industry will develop different CCA structures based on the stage of the companies involved.

In the case of Pharmasset and BMS, Pharmasset manufactures its own drug, PSI-7977, and provides it to BMS. BMS manufactures its own drug, BMS-790052, and is responsible for running the trial and covering all trial costs. A joint steering committee designed the study and will review the data. There is no commitment from either party to do future studies.

Levin noted that for some companies, it is "very important to their image" to take the lead in the study, since only one company can hold the trial IND, even when there are two investigational drugs involved. "Different companies have different imperatives," he added.

Uncharted Risks and Rewards

CCAs are "not easy to pull off – a lot of things need to come together," Glaub said.

One of the biggest risks of combining two investigational drugs is the safety. "Safety is very important," Smith said. "For us, the question is always finding a compound from a different class that has enough safety data to not put our compound at risk." Pharmasset agreed to do a CCA with BMS in part because the pharma had a big safety database for BMS-790052.

The worst-case scenario would be if a safety signal in the combination trial resulted in a clinical hold for either or both of the individual drugs. That's what happened to Idenix Pharmaceuticals Inc. when it combined two investigational HCV drugs from its own pipeline, IDX184 and IDX320, and saw elevated liver enzymes. Despite the fact that analysts remained confident in lead drug IDX184, Idenix's stock fell 47 percent. (See BioWorld Today, Sept. 8, 2010.)

Another challenge of the CCA model is its novelty. Smith said not many other companies are willing to try these deals, since rights don't change hands and big pharma often "wants more than just knowledge" at the end of the day.

Cost can also be a stumbling block. Glaub noted that each company "has its own portfolio and has allocated funds accordingly," and opportunities presented by CCAs are not factored in.

But on the flip side, CCAs can provide a cost-savings over doing a combination study in which a single sponsor must pay for the cost of both drugs. And in the long run, if each drug was only effective as part of the combination, developing them together could offer a truncated clinical path compared to completing separate Phase III studies for each compound.

Above and beyond financial considerations, the biggest benefit of CCAs is that they provide an opportunity to "work with the best companies and the best medicines," Levin said. The bottom line is figuring out if two drugs can work synergistically to tackle a disease. If that goal is met, Levin said, the makers of both components should benefit from an increased "likelihood doctors, patients and payers will use the medicines."

Since CCAs are relatively new, it is not yet clear how drugmakers will resolve issues related to commercialization. If the two drugs only work in combination, which company will file the new drug application? How will the combination be priced? Who will take the lead on sales?

But despite such uncertainties, everyone BioWorld Insight spoke to for this article was confident that CCAs will become more common in the future.

Sandifer noted that the FDA issued a guidance on combination studies last December that is "starting to lay the groundwork" for how such trials might play out along a regulatory path, although at this stage the agency said decisions will be made on a case-by-case basis.

There are a lot of unknowns, but that's not a bad thing, in Sandifer's opinion. "The industry and patients will benefit from uncharted territory," she said.

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