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33 LIFESCIENCELEADER.COM JANUARY 2015 Thus, an already big gap between KOLs and companies in cancer immunotherapy may grow even wider as business, not scientific, issues create the greatest impediment to its development and adoption. Will Big Pharma miss another historic opportunity to champion a thera- peutic revolution with cancer immuno- oncology? Can the small companies make up for pharma's inertia? Once again, as with all great endeavors, the real question is, will the optimists or the pessimists prevail? And this time, the whole world — particularly the cancer patients all of us in the industry must serve — really will be watching for the answer. l example, at a recent Congressional hear- ing concerning Sovaldi at the VA, the con- cept of the federal government "walking in" to the Gilead Sovaldi patents was dis- cussed. Payers, federal entities, and health economists are talking about value-based reimbursement — essentially paying for success only. Characteristically, pharma companies are being sluggish about jumping into the debate and openly working with payers to negotiate pay-for-success schemes for cancer immunotherapy, even though, with potentially huge increases in patient ben- efit, there is a phenomenal opportunity for profit incrementation. Ultimately the pay- ers will force the issue, so the financially successful immuno-oncology (IO) compa- nies may well be the ones that quickly plan and execute clinical trials that provide pharmacoeconomic data to support value- based, success-based reimbursement. GAME CHANGERS OR CHANGE GAMERS? Meanwhile, immuno-oncology marches on. Virtually all of the large pharmas with oncology franchises are either develop- ing IO drugs or are actively hunting for IO assets. Almost all small and midsize oncology companies have recast them- selves as cancer immunotherapy develop- ers or are struggling to get into trials with their nonimmunotherapy assets in combi- nation with anti-PD-1/anti-PD-L1. Unfortunately for the big companies, new clinical-stage IO assets among the currently exciting approaches are avail- able for licensing. As a result, the group of companies actively hunting for assets — Merck, MedImmune, Sanofi, GSK, Novartis, Pfizer, Bayer, Boehringer Ingelheim, Roche, Daichi Sankyo, Medivation, Lilly, Abbvie, Takeda, and Kyowa Hakko Kirin — are now all looking at preclinical assets. KOLs in a number of cancer indications express rapidly increasing frustration with the resistance and inaction of the large companies to start combination IO trials. Some of the world's most promi- nent KOLs have been repeatedly rebuffed by big pharmas that cite concerns about safety, intellectual property, GMP supply, "lack of clarity on approval pathway," and other rationales for inaction. The overhang of "targeted" drug devel- opment persists strongly in immunother- apy, particularly among the Big Pharmas. Virtually all of the big players are search- ing for "biomarkers" to select patients for trials or commercial use, despite the evidence that the most obvious biomark- ers, such as PD-L1 expression in tumors, do not reliably predict response. A huge misunderstanding of clinical reality persists in regard to immunother- apy biomarkers: With the targeted thera- pies, it is quite simple to look for a vari- ant gene or target molecule in peripheral fluid, but in immunotherapy, virtually all of the proposed biomarkers are in tumor biopsy tissue. Arguably, tumor biopsies will simply prove commercially imprac- tical; it is unlikely that patients, physi- cians, and payers will routinely tolerate them. Medical oncologists do not typically have the capability to do biopsies, which require referrals to interventional radiol- ogy for a dangerous, expensive, and often very uncomfortable procedure. The importance of affordability and practicality came up numerous times in our roundtable discussion. But trouble has already appeared on the horizon. Though in a different area, Gilead's premium- pricing of its liver-disease drug Sovaldi (sofosbuvir) and its successor, Harvoni (ledipasvir and sofosbuvir), has created a tough and questionable future reimburse- ment environment for new combination cancer-immunotherapy drugs. The U.S. Congress is now talking about rolling back patents for drugs deemed essential but too expensive, and the U.S. Department of Veterans Affairs is looking at a number of mechanisms for reducing the cost of specialty drugs, including oncology. For THE COMPANIES — CONVERGENCE & DIVERGENCE Like the KOLs, company leaders agreed on some issues and disagreed on others: Agreements: • IO will become dominant in cancer therapy in the relatively near future. • IO agents will be primarily used in combination. • Long way to go in understanding the underlying science • Best combinations are not currently known. No Agreement/Consensus: • Need for use of biomarkers in IO for patient selection • Commercial feasibility of autologous cell vaccines • PD-1/PD-L1 as a long-term backbone for IO • Corporate methods for selecting, developing, and commercializing IO combinations • Utility of using non-IO agents in combination with IO agents • Strategies for working with partners who own the other drugs in specific IO combinations • Universality of application of IO to all cancers • Ease of obtaining reimbursement for IO combinations (pricing) It has become difficult to be an 'oncology company' of whatever size without an effort in immunotherapy. L L E W K E LT N E R Roundtable Moderator