By Liu Changxiao

A new low of the output of innovative drugs

The 2016 Novel Drugs Summary issued by the U.S. Food & Drug Administration (FDA) shows that FDA approved 22 new molecular entities (NDE) in total by the end of December 2016, including 15 new drug applications (NDA) and 7 biologics license applications (BLA), which created a new low since 2007.

The quantity of the new drugs approved by FDA in 2016 was less than a half of the 45 new drugs approved in 2015. The industry in general believed that the quality of the new drugs was high and the proportion of biologics approved had increased, but the quantity of biologics was far less than that in 2015. 2016 was also a year witnessing the fewest new drugs approved to be marketed in the recent decade, with only 31 novel drugs approved to be marketed in the world, including 19 in the U.S., 10 in the EU, 2 in Japan, and none in China.

FDA’s Center for Drug Evaluation and Research (CDER) approved 22 novel drugs in total in 2016, including 15 NDEs and 7 new BLAs, wherein, 8 were first-in-class drugs, accounting for 36% of the total quantity approved, and 9 were approved for rare diseases, accounting for about 41% of the total quantity approved.

Quality of the new drugs had bright spots, in spite of the quantity less than previous years: the 22 new drugs included many first-in-class drugs, new-generation drugs and accurate diagnostic agents, such as Venclexta, the first protein interaction inhibitor in a real sense, and Tecentriq, the first PD-L1 antibody. Antibody drugs were back to the mainstream stage and had strong performance.

From the perspective of the therapeutic field, the anti-virus infection drugs and cancer drugs were also eye-catching. The new HCV drug Epclusa of Gilead was the variety with the largest potential among the 4 anti-infective drugs approved by FDA in 2016, which is used to treat all 6 genotypes of HCV. Regarding cancer drugs, those noteworthy included Lartruvo to treat soft tissue sarcoma, Rubraca to treat ovarian cancer, Tecentriq to treat bladder cancer, and Venclexta to treat certain patients with chronic lymphocytic leukemia.

In addition, small and medium-sized pharmaceutical enterprises were active in innovation and R&D. Pfizer and Novartis, the top 2 in global pharmaceutical sales rankings, had none in the list of new drugs marketed in 2016, while, 9 small and medium-sized pharmaceutical enterprises represented by Jazz and Clovis each had one new drug marketed, Roche, MSD and Eli Lilly each had 2 new drugs approved, and giants like AbbVie, Sanofi, Gilead and Teva each had 1 new drug approved.

The leading position of the generic drugs not shaken in the world

The history record of the new molecular drugs approved by the U.S. and EU in 2015 made 2016 full of hope. The panic for new drug patent expiration continued to spread in 2015 and 2016. The competition from generic drugs is so important to the market and patients’ demand ability that it cannot be replaced by innovative drugs. Each country has put generic drugs in an important position especially under the situation of reduction of the medical expenses. The strategy of developing generic drugs to achieve access to and economy of drug treatment is an important strategy to reduce the medical burden in many ways.

More than 95% of drugs used clinically in the U.S. are generic drugs, and so are the more than 95% drugs applied by enterprises. More than 90% drugs approved by FDA to be marketed every year are also generic drugs; Japan also gives first place to generic drugs: only the top 50 enterprises in the 1600 pharmaceutical enterprises are able to make innovative drugs, and the other more than 1500 enterprises steadily make generic drugs to reduce the diagnosis and treatment expenses of Japan and meet the needs of Japanese people; but the new drugs approved in China are behind the U.S., regardless of the NMEs or generic drugs.

There were more than 6000 generic drug varieties backlogged for approval in the U.S. in 2015. The Office of Generic Drugs (OGD) of the FDA spent a rough time in 2016 for achieving the review target, with the varieties of generic drug approved to be marketed making another record: 764 generic drug varieties were approved in total in 2016, accounting for 88% of the 868 varieties approved to be marketed in 2016, while the innovative drugs approved to be marketed accounted for less than 3%, and modified innovative drugs approved to be marketed accounted for less than 9%.

Clinical trials and review tending to be normalized

The multi-regional clinical trial (MRCT) has been widely applied in the global development of new drugs, become the main source of clinical trial data for new drug registration, and used in the new drug applications of different countries.

The foreign clinical trial data acceptable to the U.S. are divided into two kinds. The first kind is foreign non-IND clinical trial data supporting the U.S. IND or NDA: clinical trials should meet requirements of GCP standard, and onsite inspections are required by FDA to be conducted to verify the reliability of trial data. The second kind is foreign clinical trial data entirely supporting NDA: the data should apply to the U.S. population, with the clinical trials in the U.S. completed by qualified researchers, and the data should be considered reliable without going through onsite inspections, or their reliability can be confirmed by FDA through onsite inspections or other methods.

From the perspective of regulation, the registration supported with MRCT data should be reviewed from 3 aspects: one is the acceptability: the trial design scheme should be reasonable, and the data quality should meet the ethical principles and GCP requirements; two is the applicability: the resulting efficacy and safety can be used to patients of the region; three is the consistency, namely the consistency of drug effects in each region. The Extrapolation of results from clinical studies conducted outside Europe to the EU-population issued by the EU in 2016 focuses on whether the clinical trials meet the ethical principles and GCP requirements, and whether the data quality is guaranteed, in aspect of pharmaceutical product approval for marketing. Japan stresses the strict compliance with ethical principles and GCP requirements, and the Japanese drug regulation requires onsite inspection on any institution participating in clinical trials.

Significant progress of the immunotherapy

The personalized drugs approved by FDA only accounted for 21% in 2014, and the figure grew to 28% in 2015, wherein, the oncology drugs grew to 35%, which was associated with the industry’s priority review of personalized drugs. The quantity of approval of new drugs for genetic rare diseases also grew, showing the progress of the genomics and personalized drugs. More than 40% of the newly developed drugs in 2016 were personalized drugs, and this proportion will continue to grow in the future. The small molecule immunotherapy will be strongly supported by the pharmaceutical industry, and the entry of a large number of T cell activators into clinical trials is worth expecting. As the most-watched new technology, CRISPR-Cas9 is expected to be rapidly optimized the technology to become more accurate, with higher editing efficiency. All efforts to seek new gene technology have drawn attention worldwide.

The high throughput sequencing has promoted the cancer and immunology research, and the development of the individualized immunotherapy. As one of the adoptive cellular immunotherapies, CAR-T cell therapy includes modifying T cell in vitro to enable it to target tumor antigen and generate the corresponding immune response. The effects of this cell therapy in early treatment of CD19-positive leukemia are very significant, therefore, Kite and Juno, pioneers in the field, have been heavily funded by the market for the R&D and Novartis, an investor in the field, has made huge investment.

Most of the cancer immunotherapies are based on blocking the immunosuppressive pathways, for example, the mechanism of action of inhibitors targeting PD-1 and PD-L1, etc. is all blocking the immunosuppressive pathways, for the T lymphocyte to attack tumors. It is impossible for the immune checkpoint inhibitor therapy to be effective to all cancer patients, therefore, it is crucial to activate some patients’ immune response to tumors. Lycera, a biopharmaceutical company committed to developing breakthrough immunomodulatory drugs, has announced the initiation of Phase 1/2a clinical trial to test the efficacy of its cancer immunotherapy LYC-55716 in treating patients with advanced, relapsed, or refractory solid tumors. Applications of new immunotherapies like T cell therapy for hematologic neoplasm, new brain tumor treatment by cancer vaccines, and continued immunotherapy had more extensive influences on cancer patients, which was important progress of cancer treatment in 2016.

Continued momentum of merger and acquisition (M&A) and cooperation of pharmaceutical giants

Large pharmaceutical companies continued to participate in small-scale M&A or cooperation in 2016, to make up for the new products urgently needed supplementing by enterprises, and small pharmaceutical companies tried to avoid being swallowed up.

The innovation and R&D contributions of small companies have been valued by the world, which are important technical strength contributing to large companies. In 2016, Novartis benefited from the marketing of Entresto, a drug for heart failure, and the strong patent drug franchising, wherein, the market has been most optimistic about fingolimod, everolimus and nilotinib; Roche still had a significant gap with Pfizer and Novartis; Gilead has become a large pharmaceutical company from a medium-sized biopharmaceutical company; AbbVie acquired Pharmacyclics, to obtain the new anticancer drug ibrutinib that has development potential, more conductive to the upgrading of the company.

There have been increasingly more Chinese enterprises with similar development strategies which exert influences on global drug development through cooperation and M&A in recent years. There were 70 M&A cases, 60 horizontal integration cases, 2 vertical integration cases, and only 1 business transformation case of medical and pharmaceutical listed companies in China in 2016. Overall, there were more internal M&As and less cross-border M&As of pharmaceutical industry.

Original: Sciencenet