The biggest news makers and trending stories of 2015

Despite turbulent capital markets, it was another record year for biopharmaceutical company financings, both public and private. Significant advances were seen in the burgeoning, complex world of biosimilars. And the behemoth China has repositioned itself to be a drug development powerhouse, giving credence to its new status as the second largest pharma market. Even though great scientific strides were also included in BioWorld's top 10 list (CRISPR/Cas9 gene editing technology) and mega deals rocked the sector, what choked its way up to the top of the list of most impactful stories was, undeniably, the drug pricing debate. Though Martin Shkreli has been deemed the most hated man in America, his shanda tore off an infected, industry scab that no PR bandage will heal. Look for the drug pricing debate to bleed well into 2016.

1. DRUG PRICING DEBATE HITS 'TURING' POINT

It might not have been disgraced biotech CEO Martin Shkreli's intention to shine a blinding light into the face of the drug pricing debate, but that's what happened when his former company, Turing Pharmaceuticals AG, unapologetically jacked up the price of a 62-year-old antiparasitic drug by a whopping 5,500 percent, prompting U.S. lawmakers to drag the entire pharma industry into a Marathon Man-style interrogation room. (See BioWorld Today, Dec. 11, 2015.)

The sector had been getting pushback on pricing for the last few years, thanks to unrelenting criticism of Gilead Sciences Inc.'s pricey hepatitis C drugs, for example, and predictions of even higher costs as specialty pharmaceuticals comprise the majority of FDA approvals. PricewaterhouseCoopers LLP has reported that spending on specialty drugs, which totaled $81.7 billion in 2012, is estimated to grow to $401.7 billion by the end of this decade, a prospect made all the more daunting for consumers facing larger out-of-pocket expenses imposed by the Affordable Care Act. (See BioWorld Today, Sept. 24, 2015.)

Given all that, the issue was likely to remain a topic for the foreseeable future, but the unexpected move by Shkreli's Turing did what no amount of public discourse could have accomplished on its own: It forced officials to confront the issue head-on. A special Senate committee was convened to investigate the issue, and presidential hopefuls took up the mantle – a single tweet from Hillary Clinton generated a storm on both Twitter and Nasdaq – and the steady stream of negative press dented the stocks of even the most stalwart biopharmas during what was otherwise a stellar year for the sector on Wall Street. (BioWorld Insight, Sept. 28, 2015.)

2. BIOSIMILARS MAKE HEADWAY

While the first biosimilar hit the U.S. market in 2015, the FDA's early approval of Sandoz Inc.'s Zarxio in March didn't open any floodgates. Instead, several biosimilars are still awaiting approval, well past their 10-month BsUFA review time.

When the FDA approved Sandoz's biosimilar to Amgen Inc.'s Neupogen (filgrastim) in March, nearly two months ahead of the BsUFA date, it was seen as a sign that the agency was plunging full speed ahead with biosimilars. Reinforcing that view, the agency gave Zarxio a label that mirrored that of Neupogen's, with extrapolated indications and nary a mention of "biosimilar." (See BioWorld Today, March 9, 2015.)

Those early hopes for the U.S. biosimilar market have been tempered as none of the other candidates awaiting approval in 2015 has yet to make it through the FDA gate.

Other delays loomed. Zarxio's launch was pushed back nearly six months by ongoing litigation seeking to sort out the intricacies of the patent dance laid out in the Biologics Price Competition and Innovation Act (BPCIA). In a fractured decision, the Federal Circuit ruled in Amgen Inc. v. Sandoz Inc. that the BPCIA dance was optional and that biosimilar sponsors had to wait until after FDA approval before they could give the maker of the reference product the 180-day notice of commercial marketing required by the act. (SeeBioWorld Today, July 22, 2015.)

The decision is on appeal to the Supreme Court, and other lawsuits have been filed to tease out the limits of that ruling and answer other questions raised by the BPCIA.

Meanwhile, the FDA continued to shape the U.S. biosimilar path in 2015. More than a month after approving Zarxio, it finalized its first guidances, which were released as drafts in 2012. And in August, the agency issued a much-awaited, but controversial, draft guidance on biosimilar naming, proposing that a reference product and biosimilars share a core drug substance name, with each being assigned a unique, meaningless, four-letter suffix. However, the FDA has yet to deliver on its promise of guidance on labeling, extrapolation and interchangeability. (See BioWorld Today, April 29, 2015, and Aug. 28, 2015.)

The Centers for Medicare & Medicaid Services struck a blow at the newborn biosimilars market when it refused to back away from a 2016 physician payment plan for Part B drugs that places a reference biologic under one payment code while lumping all its biosimilars under another code regardless of their indications. (See BioWorld Today, July 21, 2015, and Nov. 3, 2015.)

Outside the U.S., the biosimilar market continued to grow in 2015. China's market, which has lagged behind that of India and South Korea due to pricing and regulatory issues, took a step forward when Genor Biopharma Co. announced plans to invest $40 million to build a biosimilars plant in Yunnan Province as part of a move to industrialize its trastuzumab and infliximab candidates. (See BioWorld Today, April 1, 2015, and Oct. 28, 2015.)

In Latin America where most countries are developing regulations and guidelines to facilitate the use of biosimilars, Brazil seized on the emergence of the follow-ons as the foundation of a home-grown biotech sector, with the government promising to switch its $1 billion annual purchase of imported originator drugs to biologics manufactured domestically. (See BioWorld Today, Sept. 22, 2015.)

Although biosimilars have been part of the EU health care landscape for nearly a decade, the follow-ons gained more acceptance and are claiming a larger market share. The UK's National Health Service published the first country-level biosimilars use guide in 2015 to inform finance and procurement decisions. The follow-ons also got a boost in the UK when the National Institute for Health and Care Excellence issued guidelines to support the systematic introduction of biosimilar infliximab to replace Johnson & Johnson's innovator product Remicade. (See BioWorld Today, Aug. 17, 2015, and Oct. 6, 2015.)

3. MAJOR DEALS ROCKED THE SECTOR, BUT TAX-INVERSION PARTY COULD BE OVER SOON

Pfizer Inc. in November left its New York home for an Irish domicile by combining with Allergan plc in an all-share deal valuing the latter at $160 billion and cutting Pfizer's tax rate from 25.5 percent in 2014 to 17 percent to 18 percent for the combined company – one of several whopper mergers. Allergan earlier rejected the hostile overtures of one giant specialty pharma for a deal with another, fleeing from Valeant Pharmaceuticals International Inc. into the waiting arms of Actavis plc in a $66 billion transaction that closed in March.

Pfizer, too, was busy in the first part of the year, buying Hospira Inc. in a $17 billion February tie-up that could reshape the landscape for biosimilars.

Tax inversions of the kind brought about by the Pfizer/Allergan arrangement, however, came under increasing scrutiny by the U.S. Department of the Treasury, which vowed that new guidelines would help the nation run a tighter ship. "Cross-border mergers that are done for non-tax business reasons generally strengthen the U.S. economy," the department's secretary Jacob Lew said. "It is very different, however, when mergers are designed primarily for tax-avoidance reasons."

4. FROM STRATIFIED AND PERSONALIZED TO PRECISION: OBAMA'S INITIATIVE BRINGS FOCUS TO TERMINOLOGY, RESEARCH EFFORTS

The first concrete manifestation of President Barack Obama's Precision Medicine Initiative (PMI) arrived in December with the beta launch of precisionFDA, an online portal to support development of tests to detect and interpret the millions of genetic variants that lie at the heart of disease pathology and individual response to drugs.

Also in December, 2016 funding for PMI of $200 million was confirmed, the majority of which will be devoted to assembling 1 million volunteers, representative of the U.S. population who will give a one-off consent for their data to be used repeatedly in research.

The cohort will be "a research foundation for 21st century medicine." The aim is that the combination of engaged participants and the richness of biological, health, behavioral and environmental data they contribute, will underpin a wholesale transition from one-size-fits-all, to systematically targeting therapies to likely responders, making treatment more effective and healthcare more efficient.

In addition to bringing statistical power, the cohort program will involve creating standards and infrastructure – in areas ranging from interoperability of computer systems and electronic health records, to biomarkers and biobanking – that are needed to apply precision medicine at scale in drug development and health care systems.

As PMI gets off the ground, early successes of the approach continue to accumulate, in particular, in targeted cancer therapies. However, precision medicine is not solely about new products, but also developing diagnostics that enable existing drugs to be used more appropriately.

An example of the potential to reduce health care costs while improving treatment comes from research published in December, in which using tissue databanks in Europe, U.S. scientists have come up with the basis of a test for identifying those patients with chronic kidney disease who are likely to advance the soonest.

But there is a problem in that the low cost of diagnostics means there is little commercial incentive to develop tests to underpin the precision use of marketed drugs. The matter of reimbursing a drug and its accompanying diagnostic also will need to be finessed, both for old and novel therapies.

There will be more funding to come when the 21st Century Cures Act is passed, but currently the U.S. investment looks modest in comparison to the €1 billion-plus (US$1.1 billion) that the EU as a whole has put into precision medicine, and to national programs, with the UK for example, having invested more than £1 billion (US$1.48 billion).

At a European level much of this money has gone into elements such as biobanks, bioinformatics, e-health and computational analysis. However, it is up to individual countries to apply these resources in bringing a precision medicine approach to their health care systems.

While it may have less funding for now, what Obama's initiative has done is to create a focus for orchestrating many disparate components. It also has brought coherence to the terminology, with the alternatives of personalized or stratified medicine being ditched.

Following the barrage of rhetoric, in 2016 the means will be at hand to begin the systematic development and deployment of precision medicine.

5. THE FIRST ONCOLYTIC VIRUS THERAPY GETS FDA NOD

The FDA approval in October of Amgen Inc.'s oncolytic virus therapy Imlygic (talimogene laherparepvec) for melanoma was an important milestone in the development of a therapeutic category that has taken a long time to mature. The landmark approval has stimulated further investment in other oncolytic virus developers working on next-generation technologies, including start-ups such as Toronto-based Turnstone Biologics Inc., and Oxford, UK-based Replimune Ltd., which was founded by the original team that pioneered Imlygic's development.

There is room for improvement. Imlygic, an engineered strain of herpes simplex virus 1 (HSV-1), has modest benefits as a monotherapy. It can reduce the size of inoperable skin and lymph node lesions, but it does not improve overall survival or have an effect on metastatic lesions in the bone, brain, lung or other visceral tissue.

But viral therapies are no longer being pursued as solo oncolytic agents capable of debulking tumors on a large scale. Their ability to stimulate an inflammatory milieu within the tumor microenvironment has given them a new lease of life as immuno-oncology agents that can be combined with checkpoint inhibitors and other therapies.

Amgen, of Thousand Oaks, Calif., and Merck, of Kenilworth, N.J., are planning a phase III trial of Imlygic and Keytruda (pembrolizumab), the programmed death 1 receptor inhibitor, on the back of positive interim data from an ongoing phase Ib trial (called Masterkey-265) of the two agents in advanced melanoma. There is already considerable overlap between so-called oncolytic viruses, viral vaccines and genetic engineering with viral vectors. Expect further convergence in the coming decade.

6. SUDDENLY, NASH DRUGS ARE EVERYWHERE. ARE MEGA-BLOCKBUSTERS AHEAD?

With rates of adult obesity reaching higher than 20 percent in every U.S. state and the obesity epidemic continuing to spread, nonalcoholic steatohepatitis (NASH) is expected to become ever more common. Current estimates suggest that up to 287 million people worldwide might have the condition, a potential waypoint to cirrhosis, and a "mega-blockbuster" market opportunity, according to Morningstar analyst Stefan Quenneville, who expects the market could be worth $30 billion-plus (though sales would more likely be just $10 billion by 2024 due to potential drug launches being hindered by the slow moving nature of the disease and current limited diagnostic tools, he said).

With that kind of money of the table, there's no shortage of potential new therapies in development.

Intercept Pharmaceuticals Inc., Galectin Therapeutics Inc. and Gilead Sciences Inc. were just a few of the sponsors behind 39 companies that started NASH trials in 2015, according to Thomson Reuters Cortellis Clinical Trials Intelligence. Others detailed new data and plans at the American Association for the Study of Liver Diseases Annual Meeting in San Francisco in November.

NASH is often called the "silent" liver disease because it can happen without causing any symptoms. By contrast, expect the busy race to be among the first to treat it to generate plenty of noise in the year ahead. (See BioWorld Today Nov. 17, 2015, and BioWorld Insight, Sept. 28, 2015.)

7. BIOMARIN AND SAREPTA RACE FOR FDA APPROVAL OF DMD THERAPY

The bumpy road of research into treatments for the orphan indication Duchenne muscular dystrophy (DMD) may have reached an important waypoint in 2015 with two new drug application (NDA) filings for exon 51-skipping products, Biomarin Pharmaceutical Inc.'s Kyndrisa (drisapersen) and Sarepta Therapeutics Inc.'s eteplirsen.

Both candidates await FDA decisions within the next two months: early January for drisapersen, and Feb. 26, 2016, for eteplirsen, which also has a Jan. 22 advisory committee meeting scheduled. The committee discussed in November the drisapersen NDA, pitting skeptical panel members against enthused parents who say their sons' real world experiences after taking drisapersen (dancing, riding bikes, hugging) outweigh the meager 3 percent increase in dystrophin from baseline and the panel's doubts over the use of dystrophin as a biomarker. In one study, dystrophin results favored placebo, and some patients without measurable dystrophin displayed more function than those with higher levels, the committee said.

Drisapersen and eteplirsen address an estimated 13 percent of all patients with the neuromuscular disorder caused by mutations in the dystrophin gene. Both candidates showed improvement in the six-minute walk distance endpoint, although the endpoint itself – required for approval – limits the research by needing to enroll only ambulatory patients.

Biomarin, of San Rafael, Calif., completed its NDA submission in April, a couple months before Sarepta, following its January acquisition of drisapersen-developer Prosensa Holding NV, of Leiden, the Netherlands. It also prevailed over Sarepta, of Cambridge, Mass., in September in a patent dispute regarding the use of exon 51 antisense oligonucleotides to treat DMD.

Gaining ground behind the exon-skipping candidates is PTC Therapeutics Inc.'s Translarna (ataluren), which has conditional approval in the EU. The South Plainfield, N.J.-based company said in October, upon release of phase III data, that it planned to complete a rolling NDA submission by the end of 2015.

8. CHINA IS PRIMED FOR MEANINGFUL DEVELOPMENTS

2015 is the year that China got serious about drug innovation. Still lacking a global blockbuster – but with the Glaxosmithkline plc corruption scandal a year behind it – the focus returned to what China's government has invested so heavily in: China Champions.

The nation's first Nobel Prize for Medicine, awarded to Youyou Tu for the traditional Chinese medicine-inspired anti-malarial, artemisinin, gave a welcome boost. But its invention in the 70s highlighted where things have gone awry in the intervening decades, with over emphasis on patents and papers, and a dearth of effective new drugs.

But China does not lack daring in the lab. When Junjiu Huang, of Sun Yat-sen University, used CRISPR/Cas9 to edit the genes of a non-viable human embryo, he propelled the human gene-editing debate kicking and screaming onto a global stage.

More quietly, but more important for China, the State Council gave the green light to overhaul the regulatory system making it finally feasible to get new drugs approved in a timely manner, but also tipping the playing field toward local companies. These changes will take three to five years for the CFDA to implement, but big pharmas are already lining up beside leading local firms to bring in their novel assets and many are investing heavily in made-in-China manufacturing to comply.

Local biotechs have also proven they can rake in the dough, even without the China market: Jiangsu Hengrui Medicine Co. Ltd., of Shanghai, and Suzhou-based Innovent Biologics Inc. inked out-licensing deals for early stage candidates with U.S.-companies hovering in the billion dollar range – setting a new benchmark for the value of Chinese innovation and showing that generics are not the only way to profits.

8. CRISPR'S GROWING UP FAST

The CRISPR/Cas9 gene editing technology, which has been generating excitement among scientists for a few years now, made its way into the general public's consciousness with an April report by Chinese scientists that they had edited the germline of human embryos to correct a hemophilia gene. That report, as well as work whose ultimate goal is to release CRISPR-modified animals into the wild in so-called "gene drives" that can spread a desirable gene – for example, for malaria resistance – through a population, prompted discussion and ultimately, a December summit co-sponsored by the national academies of China, U.S. and the U.K. where the beginnings of a legal, ethical and policy framework for research using the CRISPR/Cas9 technology were established.

Most CRISPR applications are noncontroversial, however, and 2015 brought several improvements to the technology, as well as a steady stream of reports of new findings based on its use. (See BioWorld Today, Feb. 9, 2015, May 21, 2015, and Sept. 21, 2015.)

No promising new technology could be complete without a patent battle, and so it is with CRISPR. In April, the University of California, Berkeley, asked the U.S. Patent and Trademark Office to reconsider a series of patents it awarded to The Broad Institute of Harvard and Massachusetts Institute of Technology.

Collectively, the biopharma industry is not waiting for the outcome of that case to forge ahead. Crispr Therapeutics AG, co-founded by CRISPR pioneer Emmanuelle Charpentier, and Editas Medicine Inc., co-founded by her rival Feng Zhang, both raised funds in 2015, and in October, Crispr Therapeutics and Vertex Pharmaceuticals Inc. announced the largest-ever deal in the space, worth a potential $2.6 billion, with $105 million up front. Crispr then capped its year by announcing a $335 million deal with Bayer AG in December.

10. RECORD YEAR FOR PUBLIC OFFERINGS DESPITE TURBULENT CAPITAL MARKETS

Although the sector ran into some severe turbulence in the second half of the year caused by the negative sentiment swirling around the issues of high drug pricing it certainly had no noticeable effect on the ability of biotech companies to raise capital to fuel their product development programs.

Public offerings, in fact, generated almost $50 billion in 2015 – an amount that swamps the total of all forms of financing, both public and private, generated each year dating back to 2000. The only total close to this amount was the $26 billion raised by public offerings in 2014. This year private financings were also on fire generating more than $10 billion, over twice the amount companies normally generate in a single year. In all biotechs raised an incredible $68.4 billion setting a new high water mark for the industry.

While the record number of U.S. biopharma IPOs were completed in 2014 – 78 – was going to be a hard act to follow, 54 companies successfully completed their U.S. listings this year generating almost $6 billion despite the uncertain capital markets. It was also a year that European biotechs plugged into Wall Street representing 20 percent of the total biotech IPOs including anti-infective developer Nabriva Therapeutics AG, of Vienna, which raised more than $100 million from an IPO of American depositary shares.

EBOLA, WHERE ARE WE NOW? A LOOK BACK AT 2014'S TOP STORY

The development of a vaccine for Ebola that looks to be effective is among the most important pieces of 2015 news with no immediate consequences.

It took all of 2015 for the Ebola outbreak to truly end. On Dec. 29, the World Health Organization announced that Ebola transmission had ended in Guinea, where the epidemic started almost exactly two years ago. As of Dec. 20, 2015, this largest-ever outbreak had caused 28,637 reported cases and 11,315 deaths. An end to transmission means that there have been no new cases for 42 days after the last case's recovery.

"This is the first time that all three countries – Guinea, Liberia and Sierra Leone – have stopped the original chains of transmission that were responsible for starting this devastating outbreak two years ago," said Matshidiso Moeti, WHO Regional Director for Africa, announcing the end of transmission.

But the epidemic was already on the wane in July, when data showing the effectiveness of Merck & Co. Inc.'s/Newlink Genetics Corp.'s VSV-EBOV vaccine were published in The Lancet on July 31, 2015.

For a while, there had been doubts whether there were would still be enough Ebola infections to see a difference between vaccination and control groups. (See BioWorld Today, April 13, 2015.)

But while there was not enough data to file for approval of the vaccine, the trial – partly due to its use of an innovative ring strategy that vaccinated the contacts of infected individuals – was able to show that when it was administered as soon as possible after they had been identified, VSV-EBOV was 100 percent effective in protecting contacts and contacts of contacts, of patients diagnosed with Ebola infection, with no infections reported among 2,014 individuals in 48 rings.

In the control arm, where vaccination of 2,380 contacts in 42 rings was delayed for 21 days after a case's diagnosis, 16 developed an Ebola infection (95 percent CI 75 -100.0; p value = 0.0036).

The results are a success for both the VSV-EBOV vaccine and the ring strategy used to test it. Ring vaccination could be a good countermeasure to prevent future epidemics from reaching the magnitude of the 2014/2015 West African outbreak.

They also show that vaccines are a bright spot in the otherwise bleak world of the fight against infectious disease.

Scientists have been sounding the alarm of an impending return to the pre-penicillin era for some time now. December marked another milestone on that road as plasmid-mediated colistin resistance was reported in both Asia and Europe in December, meaning that there are now resistance genes to what was previously an antibiotic of last resort to gram-negative infections. (See BioWorld Today, Sept. 22, 2015, Dec. 2, 2015, and Dec. 8, 2015.)

But while even a pound of cure may no longer do any good in the all-too-near future, the picture looks much brighter as far as prevention is concerned.

The first malaria vaccine was approved in July by the EMA, followed by the first dengue vaccine approval in December in Mexico and Brazil. (See BioWorld Today, July 27, 2015, and Dec. 11, 2015.)

At the International Conference on Antimicrobials and Chemotherapy and the International Congress of Chemotherapy (ICAAC/ICC) 2015 annual meeting in September, Rino Rappuoli, chief scientist at Glaxosmithkline plc vaccines, told his audience there is currently "an explosion" of new technologies that will allow vaccines to be made for diseases that have so far resisted those efforts. "I believe that we will see a revolution in vaccines over the next decade," he said.

BioWorld staffers Jennifer Boggs, Anette Breindl, Karen Carey, Shannon Ellis, Michael Fitzhugh, Nuala Moran, Randy Osborne, Marie Powers, Mari Serebrov, Cormac Sheridan and Peter Winter contributed to this report.

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