Randi Hernandez was science editor at Pharmaceutical Technology from September 2014 to May 2017.

Randi Hernandez

	The Office of the United States Trade Representative (USTR), an agency that negotiates with foreign governments to create trade policy agreements, publishes a report each year detailing challenges American innovators face in overseas markets. Pharmaceutical manufacturing trade group PhRMA recently contributed comments to USTR’s 2017 Special 301 Report outlining the specific actions that threaten biopharmaceutical innovation in the United States.

	A new focus of the Trump administration is the 

 which seeks to increase US exports to other countries and enforce import tariffs on goods coming in from other countries. In its comment to USTR, PhRMA essentially expressed its support of the 

pursuit of a foreign policy based on American interests

	The new trade policy from the White House focuses on the abandonment of the Trans-Pacific Partnership (TPP) and the renegotiation of North American Free Trade Agreement (NAFTA) policy. The White House states on its website, “If our partners refuse a renegotiation that gives American workers a fair deal, then the President will give notice of the United States’ intent to withdraw from NAFTA.”

	PhRMA’s observations in the report mirror some of Trump’s recent sentiments about the world benefitting from drugs developed in the US at the country’s expense. Mark Grayson, deputy vice-president of public affairs at PhRMA, wrote in a 

 that the trade group would like USTR to address the barriers to market penetration overseas and take action to “ensure America's trading partners live up to their intellectual property and market access commitments in global, regional, and bilateral agreements."

	PhRMA specifically expresses concern about how countries overseas regard the intellectual property (IP) protection of biopharmaceutical inventions manufactured in the US. They note that pharmaceutical products exported overseas are subject to "serious intellectual property and market access barriers.” The group identified 18 countries with the most significant barriers to effective IP protection, with a special focus on Canada, China, Colombia, and India. PhRMA has good reason to protect revenue from biopharmaceuticals in foreign markets: According to figures cited within the report, the industry exported $55 billion in biopharmaceuticals in 2015, “making the sector one of the top US exporters among intellectual property-intensive industries.”

	Several countries enact regulations for the trade and development of pharmaceutical products that appear to contradict with existing World Trade Organization (WTO) policies and US trade agreements, wrote PhRMA. Current policies require agencies to issue patents for medicines that are “new, involve an inventive step, and are capable of industrial application,” but some countries are not fulfilling their commitments to comply with existing trade contracts.


	PhRMA argued “restrictive patentability criteria” in foreign markets negatively affect the issuance of new patents for biopharmaceuticals. Furthermore, weak enforcement of US patents overseas and compulsory licensing-wherein a country allows the manufacture of crucial medicines without the consent of the patent holder-undermines the benefits and impact of patent ownership.  

	Restrictive criteria prevent patent assignments in Canada, Argentina, the Philippines, Indonesia, Argentina, India, and China, says PhRMA. In Canada, the invention listed in a patent filing must prove utility (i.e., that the invention accomplishes what it sets out to do), before the patent can be filed. Utility can only usually be demonstrated after clinical trials have concluded, which delays the filing of the patent unnecessarily, notes PhRMA.

	Argentina restricts patents on new dosage forms and combinations of drugs. Thus, formulation improvements do not typically allow for patent term extensions. Laws in the Philippines and Indonesia prohibit new forms and uses of already-approved medicines. India prevents patents on known substances unless the patent demonstrates “enhanced therapeutic efficacy.”

	Long-term maintenance of biopharmaceutical patent ownership in China is difficult, as China does not “consistently” allow innovator companies to present new data in patent prosecution proceedings that prove the patent is innovative if the experimental data happened to be collected after the patent was initially filed.


	Patent examination delays are common in Brazil, Thailand, India, and Venezuela; it can take many years to secure patents in these areas of the world for various reasons related to workflow. In Brazil, patents need to be reviewed by the patent office and the Brazilian Health Surveillance Agency (ANVISA), which PhRMA says unreasonably protracts the patent application process.

	Delays in regulatory approvals and infrequent updates to reimbursement policy and decisions in various countries cause decreased patient access to medications, according to PhRMA. Single-payer systems-in which the government has the power to negotiate drug prices-prevent manufacturers from realizing full market access, the agency concludes.

Compulsory licenses and in-country manufacturing


	PhRMA contends that compulsory licenses should be granted only in emergency situations as a “last resort”-and stakeholders should be able to weigh in on the decisions to grant such licenses. Currently, India and Indonesia can issue compulsory licenses, and Chile, Colombia, Peru, Russia, Turkey, and Vietnam are considering similar legislation. PhRMA argues that alternatives to compulsory licensing-such as voluntary licenses granted by manufacturers, drug donation, non-assert declarations (where a patent holder agrees not to enforce patents in certain areas), and differential pricing programs-simultaneously protect innovator companies and increase access to medicines.

	The agency asserts that some countries exploit compulsory licenses and use the licenses primarily to set up local manufacturing facilities “at the expense of manufacturers and jobs in the United States and elsewhere.” In fact, policy in some countries favors local manufacturing heavily and bans foreign medicine procurement when competing products can be found locally. PhRMA points to China as an example, where regulatory data protection is awarded to drugs that are first launched and manufactured domestically; China does not provide similar protections for drugs that have origins in the US.

	Indonesia has a new patent policy that automatically permits compulsory licenses for medications if, by three years following initial approval, the patent holder has not set up manufacturing capabilities within the country. Indonesia further reinforces local production initiatives by issuing the requirement that any foreign biopharma company wishing to import its drugs must also transfer its technology and manufacturing knowledge to an Indonesian firm so that the country will be capable of producing the drugs in-country within five years, PhRMA reports.

	By not recognizing any good manufacturing practice (GMP) certifications obtained outside of Turkey, the country effectively bars all pharmaceutical imports, writes PhRMA, unless the importing country coordinates a mutual recognition agreement that conforms with the quality standards of inspection in Turkey.

	Lastly, PhRMA writes that new policy in Russia limits drug procurement to manufacturers that are members of the Eurasian Economic Union (EAEU), provided there are at least two EAEU drug makers for a drug class.


	Should a patent be invalidated in Australia, and a generic equivalent is subsequently released, the innovator company must compensate Australia’s Pharmaceutical Benefits Scheme (PBS) for the higher prices PBS paid during the period in which the patent was considered valid. Additionally, PhRMA points out that, in Australia, the price of a branded product automatically drops to match the price of competing generics that enter the market. No damages are granted to innovator companies, however, if competing products are launched prematurely (i.e., if the innovator company ends up successfully defending its patent). As a result, says PhRMA, the Australian drug agency creates an “inappropriate conflict of interest by permitting the same government that examined and granted a patent to seek damages if that patent is later ruled invalid or not infringed.” In addition, while US trade agreements dictate that innovator companies be notified when a competitor wants to introduce a generic, Australia does not comply with this rule. Similarly, innovators are not notified when marketing applications are filed for competing therapies in China, India, and Russia. Processes to help an innovator defend its rights to a patent are slow and drawn out in Peru and Mexico, PhRMA explains in the document.

	Although regulatory data protection (RDP) for biologics in the US is 12 years, Algeria, Argentina, Brazil, China, Ecuador, Egypt, India, Turkey, and Venezuela do not provide this protection for biologics manufactured in the US. RDP is not granted for drugs touting new formulations, dosages, indications, or compositions in Chile, and data protection in Mexico and Peru is only available for small-molecule therapies (not for biologics). As a result of a 2014 law passed in Canada, the Health Minister there has the right to share a manufacturer’s regulatory data freely, without reserve.

	The WTO Trade Agreement-which was forged in March 1994 between the US and 33 other countries-guaranteed that no import duties be imposed on pharmaceutical products. For countries that did not participate in the agreement, however, high import tariffs imposed on the US are crippling the reach of certain medications, PhRMA maintains. China, India, Brazil, Argentina, Russia, and Thailand impose such taxes. Despite the fact that India exports the bulk of its generic drugs and APIs to the US, it also employs an average import tax of nearly 10% for US-manufactured biologics, argues PhRMA. Taken together, Brazil’s import taxes can increase the price of medicines by nearly 34%. It is important to note, however, that the World Health Organization (WHO) concluded in 

 that when compared with gross domestic product (GDP), pharmaceutical tariffs generated an insignificant amount of revenue; WHO said approximately 92% of countries generate less than 0.1% of GDP through pharmaceutical tariffs.

	In its comments for the Special 301 Report, PhRMA urges USTR to take an aggressive approach in the protection of America’s IP. PhRMA calls for a ramping up of patent enforcement activities in countries that do not already comply with regional and bilateral trade agreements, and expresses the need for increased global cooperation. The agency appeals to USTR to fight for transparency in the pricing and reimbursement of pharmaceuticals by overseas payers. Lastly, PhRMA beseeches USTR to fight the spread of counterfeit medications.

	Challenging patents: Small-molecule generics vs. biopharmaceuticals

	Patents promote competition in the pharmaceutical marketplace, wrote PhRMA, mostly because patent protection requires that innovators disclose their inventions to the world to obtain this protection. While this may be true for small-molecule generics, biopharmaceutical drugs and the patents that protect their manufacture are a bit more challenging. As Jacob Sherkow, JD, associate professor, Innovation Center for Law and Technology, New York Law School recently 

, patents on biopharmaceuticals are often filed early in the discovery process and are not described in enough scientific detail for competing manufacturers to reproduce and/or reverse engineer similar products. Sherkow attests the deficiencies in the breadth of the disclosure that appears in filed patents contributes to costly, often irreproducible research by potential competitors. Considering this point, companies that may attempt to compete against innovator drugs may not be able to secure approvals for drugs in the same therapeutic class because they cannot replicate the compounds or master the methods described in innovator patent documents. Some could argue, then, that current patent law (and the way biopharmaceutical patents are written) actually dissuades competition.

	Some experts point out that the concepts of moving more manufacturing jobs back to the US and lowering the price of drugs domestically may be diametrically opposed. Repatriation is just part of Trump’s recent pledge; the Trump administration also seeks to 

 for American workers once jobs return to the US. However, an increase in wages may mean the overall cost of manufacturing increases, potentially making drugs more expensive to Americans domestically.
	
	Source: 

Articles

PhRMA submits comments to the The Office of the United States Trade Representative encouraging protection of US innovation in foreign markets.

PhRMA Urges USTR to Ramp Up Patent Enforcement Activities Overseas

 highlighted antibody-based therapeutics that have set Prescription Drug User Fee Act (PDUFA) dates in 2017. These dates have been disclosed by the companies developing the drugs, and the forecasted approval dates were drawn directly from company-disclosed information (e.g., press releases, company presentations).

, in collaboration with life-science commercial intelligence firm 

, highlights product candidates that have 2017 launch dates based on broker models for the products, which identify 2017 as the first year in which sales will occur for the products. In short, all of the following products are in Phase III trials-and may be eligible for regulatory approval in 2017-but may not have publically announced PDUFA dates.

	The following group of mAbs may also receive regulatory approval in 2017, but because not all companies disclose PDUFA dates, it is unclear when exactly each therapy will be considered for regulatory review. The therapies, however, could be found in company-disclosed estimates of sales earnings and Wall Street forecasts.

-Co-developed by AstraZeneca and Kyowa Hakko Kirin Co., this glycoengineered anti-eosinophil antibody targets cytokine IL-5 and is being investigated for its efficacy in the treatment of severe asthma in patients whose symptoms are not adequately controlled with inhaled corticosteroids or long-acting beta agonists. In a study published in 

, benralizumab successfully reduced asthma exacerbations in patients with high levels of eosinophils in their blood (1).

	GlaxoSmithKline’s Nucala (mepolizumab) and Teva’s Cinqair (reslizumab), which are both FDA-approved drugs that inhibit IL-5, are similar to benralizumab. Mepolizumab and reslizumab, however, target the IL-5 molecule directly, whereas benralizumab targets the IL-5 receptor. "By targeting the IL-5 receptor, benralizumab depletes eosinophils directly, and our studies show that eosinophil counts were nearly completely depleted by week 4 of treatment," said Eugene Bleecker, MD, professor at the Center for Genomics and Personalized Medicine, Wake Forest School of Medicine, who served as lead author of the SIROCCO trial investigating benralizumab, in a 

press release (1). Mepolizumab and reslizumab are indicated every four weeks; treatment with benralizumab in the four-week cohort reduced eosinophil levels but did not confer reduction of asthma symptoms. There was only a significant reduction in patient-reported asthma symptoms when treatment occurred every eight weeks (compared with placebo at week 48) (2, 3). Although this could be considered a treatment drawback, investigators viewed the eight-week cycle as a potential advantage, saying in a linked comment that lower-dose, less-frequent dosing of IL-5 could be economically advantageous (4).

 (ABT-414)-This investigational agent is actually an antibody-drug conjugate. Developed by AbbVie, it consists of an epidermal growth factor receptor (EGFR) IGg1 mAb (depatuxizumab) conjugated to the tubulin inhibitor monomethyl auristatin F via a stable maleimidocaproyl linker. FDA gave the medication an Orphan Drug status in 2014 for the treatment of glioblastoma multiforme, a type of brain cancer. It also received a Rare Pediatric Disease Designation from FDA for Diffuse Intrinsic Pontine Glioma (DIPG)-a condition characterized by tumors at the base of the brain-based on the proposal of a nested, sub-study of ABT-414 in adults with recurrent EGFR-amplified glioblastoma (5).

 (MORAb-003)-Farletuzumab is a humanized mAb that binds to folate receptor-alpha, which is expressed in 80% to 100% of epithelial ovarian cancers. It is being studied in combination with carboplatin and a taxane for the treatment of platinum-sensitive ovarian cancer. In 2013, farletuzumab did not meet the study’s primary endpoint, which was progression-free survival (PFS) (6). It was revealed in the study that patients with low levels of CA125, a protein produced by cancer cells, responded best to treatment with farletuzumab. In response to this finding, Morphotek initiated a Phase II trial, MORAb-003-011, to further investigate the potential clinical benefit observed in the patients with a low CA125 level (7, 8).

-Ibalizumab is certainly of interest, if judging by the number of companies that are involved in its development. Three co-developers are counted as cooks in the kitchen, including Theratechnologies, TaiMed Biologics, and The Aaron Diamond AIDS Research Center. Treatment with this anti-CD4 mAb for multidrug-resistant HIV-1 produced a significant reduction of viral load in Phase III clinical trials, and is likely to be reserved for heavily treated patients who have developed extensive resistance to other antiretroviral classes. It is the first mAb-based treatment being investigated in the treatment of HIV. Unlike retroviral medications, which work by inhibiting replication of the HIV virus, ibalizumab binds to the second extracellular domain of the CD4 receptor, preventing the virus from entering the CD4+ immune cells (9).  Ibalizumab was granted Breakthrough Therapy designation, an Orphan Drug status, and a Fast Track designation from FDA.

-Pfizer and UCB’s inotuzumab ozogamicin is an investigational agent for adults with relapsed/refractory acute lymphoblastic leukemia (ALL). It is an antibody-drug conjugate (ADC) composed of a mAb that targets CD22, an antigen found on the surface of cancerous B cells in many patients. The mAb is linked to cytotoxic antibiotic agent calicheamicin. Inotuzumab ozogamicin received a Breakthrough Therapy designation from FDA in 2015 (10).

	In 2016, the drug met its primary endpoint (complete response) in the Phase III INO-VATE ALL study and was found to be superior than treatment with standard chemotherapy. But, the drug did not significantly extend overall survival (the secondary study endpoint) compared with chemotherapy. In addition, veno-occlusive liver disease (VOD) occurred more frequently in patients treated with inotuzumab ozogamicin than in the chemotherapy cohort (11% vs. 1%) (11, 12).

-In development for the treatment of a disorder involving phosphate metabolism that causes rickets, called X-linked hypophosphatemia, burosumab (KRN-23) is co-owned by Ultragenyx Pharmaceutical Inc. and Kyowa Kirin International. The drug candidate seeks to reduce the activity of FGF23, a hormone instrumental in regulating phosphate excretion by the kidneys. The companies plan to submit a biologics license application (BLA) to FDA for KRN23 in the second half of 2017 (13).

-This IL-6-receptor inhibitor was originally projected by some sources to gain regulatory approval in 2015, and then in 2016, but is now expected to have a potential approval and launch in late 2017. Sarilumab received a Complete Response letter from FDA in 2016 and is currently addressing cGMP manufacturing issues related to that letter (14). Meanwhile, sarilumab was approved by Health Canada on February 2, 2017 under the trade name Kevzara (15).

	The mAb from Sanofi and Regeneron works by blocking the binding of IL-6 to its receptor and interrupting the cytokine-mediated inflammatory signaling cascade. Clinical trials with the investigational compound revealed x-ray data that showed 90% inhibition of structural damage to joints.

	Sarilumab is likely to compete with Roche/Chugai's IL-6 inhibitor Actemra (tocilizumab)‎ and with the investigational anti-IL-6 mAb sirukumab.

- XBiotech's Xilonix is being tested in clinical trials for the treatment of advanced colorectal cancer that is refractory to the current standard of care. The investigational therapy received Fast Track designation from FDA (16).

	It consists of MABp1, an antibody that targets interleukin 1α; interleukin 1α is responsible for driving inflammatory signals within the tumor microenvironment. MABp1 is being investigated for its effect on symptoms of colorectal cancer as well as its ability to treat cachexia and the associated muscle loss, fatigue, appetite loss, and pain that is characteristic of patients with colorectal cancer. There are two Phase III trials that are ongoing for the treatment of colorectal cancer: The first is studying Xilonix for a non-traditional endpoint (one measured by combined objective and self-reported measures of symptom control), and the second study is looking at the drug in relation to overall survival (17). For the “novel” endpoint of improving tumor-related symptoms, Xilonix demonstrated a clinical benefit (18). In 2012, Xilonix received a Fast Track designation from FDA for the treatment of wasting syndrome (19).

 388 (10056) 2128–2141 (Oct. 29, 2016).
	2. E.R. Bleecker et al., 

 388 (10056) 2115–2127 (Oct. 29, 2016).
	3. AstraZeneca, "Benralizumab Phase III Trials Show Positive Results in Severe Asthma," Press Release, Sept. 5, 2016.
	4. M. Castro and L.B. Bacharier, 

 388 (10056) 2059–2060 (Oct. 29–Nov. 4, 2016).
	5. AbbVie, "AbbVie Receives US FDA Rare Pediatric Disease Designation for Investigational ABT-414 for the Treatment of a Type of Pediatric Brain Tumor Known as Diffuse Intrinsic Pontine Glioma (DIPG)," Press Release, July 11, 2016.
	6. Eisai, "Eisai Announces Results of Phase III Study of Anticancer Agent Farletuzumab in Patients with Relapsed Platinum-Sensitive Ovarian Cancer," Press Release, Jan. 11, 2013.
	7. Morphotek, "Morphotek Announces Publication of Phase 3 Results from MORAb-003-004 Trial in Platinum-Sensitive Ovarian Cancer Patients," Press Release, Apr. 18, 2016.
	8. I. Vergote et al., 

 34 (19) 2271–2278 (July 2016).
	9. Theratechnologies, "Theratechnologies Announces Results from the Last Pivotal Phase III Trial of HIV Long Acting Biologic (LAB) Investigational Antiretroviral Ibalizumab," Press Release, Nov. 10, 2016.
	10. Pfizer Oncology, "Inotuzumab Ozogamicin Fact Sheet," 

www.pfizer.com/files/news/esmo/ESMO2016_Pipeline_Fact_Sheet_Inotuzumab.pdf

, accessed Feb. 1, 2017.
	11. Pfizer, "Pfizer Announces Final Results from Inotuzumab Ozogamicin Pivotal Phase 3 Study in Adults with Relapsed/Refractory Acute Lymphoblastic Leukemia," Press Release, June 12, 2016.
	12. H.M. Kantarjian et al., 

 375, pp. 740–753 (June 12, 2016).
	13. Ultragenyx, "Ultragenyx and Kyowa Kirin International Announce Marketing Authorization Application for KRN23 Filed and Accepted for Review by European Medicines Agency," Press Release, Jan. 5, 2017.
	14. Sanofi, "Sanofi and Regeneron Receive Complete Response Letter from FDA for Sarilumab, an Investigational Treatment for Rheumatoid Arthritis," Press Release, Oct. 28, 2016.
	15. Regeneron, "Regeneron and Sanofi Announce First Approval of Kevzara (sarilumab) for the Treatment of Moderately to Severely Active Rheumatoid Arthritis in Adult Patients by Health Canada," Press Release, Feb. 1, 2017.
	16. XBiotech, Inc., NCT02138422, "A Phase 3 Study to Evaluate Xilonix as an Anticancer Therapy in Patients with Symptomatic Colorectal Cancer," 

https://clinicaltrials.gov/show/NCT02138422

, accessed Feb. 1, 2017.
	17. XBiotech, Inc., "A Phase III Study of Xilonix in Patients with Advanced Colorectal Cancer (XCITE)," https://clinicaltrials.gov/show/NCT01767857, accessed Feb. 1, 2016.
	18. T. Hickish et al., 

 18 (2) 192–201, (February 2017).
	19. XBiotech, "XBiotech Receives Fast Track Designation from FDA for Anti-Cachexia Drug Xilonix," Press Release, Oct. 3, 2012.

Evaluate and BioPharm International highlight the antibody-based therapeutics that may have 2017 launch dates in the United States.

Therapeutic Antibodies to Track in 2017, Part II

In 2016, 7 of the 22 new molecular entity (NME) and new therapeutic biological product approvals by FDA were antibody-based medications: Merck’s Zinplava (bezlotoxumab), Eli Lilly’s Lartuvo (olaratumab), Biogen’s Zinbryta (daclizumab), Genentech’s Tecentriq (atezolizumab), Teva’s Cinqair (reslizumab), Eli Lilly’s Taltz (ixekizumab), and Elusys’ Anthim (obiltoxaximab) (1). Although that is fewer monoclonal antibodies (mAbs) than were approved in 2015 (9 mAbs approved)-when considered as a percentage of the total approvals-there was a larger percentage of antibody-based products in 2016 than in 2015; antibody-based therapeutics were approximately 32% of NME approvals in 2016. For 2017, life-science commercial intelligence firm 

, predicts that FDA may grant marketing approval to somewhere in the range of 8–16 antibody-based investigational candidates.

	The first portion of mAbs that we highlight for 2017 are those that have concrete Prescription Drug User Fee Act (PDUFA) dates in 2017. These dates have been disclosed by the companies developing the drugs, and the forecasted approval dates are drawn directly from company-disclosed information (e.g., press releases, company presentations). As such, there may be products that are filed or in Phase III that are not included in this article, due to the lack of information regarding approval/launch dates.

	In the second section of this article, the mAbs highlighted are those that have 2017 launch dates based on broker models for these products, which show 2017 as the first year of forecasted sales for the products. All of the products in the second section are in Phase III trials-and may be eligible for regulatory approval in 2017-but may not have publically announced PDUFA dates.

	Although drug efficacy was not an inclusion requirement in the selection of mAbs that were likely to gain approval, 

 did review and include some efficacy findings from clinical trials, wherever they were applicable.

-This mAb that binds to the IL-17 receptor for the treatment of psoriasis got some bad press in May 2015 when Amgen dropped out of the co-development project with AstraZeneca after clinical-trial results suggested that the drug was associated with suicidal ideation in patients. Valeant took over the United States commercialization and development of the project in September 2015. IL-17 inhibitors have been shown to clear plaques more efficiently than anti-tumor necrosis factor (TNF) therapies, which are first-line therapies for psoriasis (2). Other FDA-approved IL-17 inhibitors include secukinumab and ixekizumab‎. Although Brodalumab had an original PDUFA date of Nov. 16, 2016, its new date is  Feb. 16, 2017. In July 2016, an FDA panel recommended the therapy for approval (3).

-Roche’s ocrelizumab, which will go by the trade name Ocrevus if approved, is being developed to treat relapsing multiple sclerosis (MS) and primary progressive MS (PPMS). FDA granted the product a Breakthrough Therapy designation in February 2016 (4). In clinical trials, ocrelizumab was shown to be superior to interferon beta-1a, a widely used treatment for relapsing forms of the disease. There are currently no approved treatments for the progressive form of the disease. Ocrelizumab is designed to selectively target CD20-positive B cells that are thought to contribute to myelin and axonal damage. It works by binding to CD20 cell-surface proteins on B cells and blocking their action. Because ocrelizumab does not bind to stem cells or plasma cells, Roche says the immune system will remain somewhat intact following the elimination of mature B cells. FDA extended review of the application for ocrelizumab so that Roche could provide extra data on the commercial manufacture of the investigational agent.

-Sanofi and Regeneron’s first-in-class dupilumab in under investigation for the treatment of eczema/atopic dermatitis, for which it received Breakthrough Therapy status from FDA in 2014 (5, 6). The companies are also investigating the drug for the treatment of asthma, chronic sinusitis, and eosinophilic esophagitis. The drug, approved by the European Medicines Agency (EMA) as Dupixent, is an IL-4Rα antagonist that inhibits the biological effects of both IL-4 and IL-13, two cytokines responsible for eliciting an immune response (7). In clinical trials, dupilumab was shown to provide significant improvement in the clinical signs and symptoms of atopic dermatitis compared with existing topical treatments or placebo (8, 9).

-AstraZeneca/MedImmune’s durvalumab was granted a Breakthrough Therapy status from FDA in February 2016 and a Priority Review status in December 2016 for the treatment of urothelial cancer in patients whose disease has progressed following treatment with platinum-based chemotherapy (10). Durvalumab is also being tested in combination with other products for the treatment of non-small cell lung cancer (NSCLC), head and neck cancers, gastric cancer, pancreatic cancer, hepatocellular carcinoma, and blood cancers in more than 30 ongoing clinical trials. This anti-PD-L1 IgG1 investigational therapy works by blocking the interaction of PD-L1 with both PD-1 and CD80 on T cells, effectively blocking the “cloaking” mechanism that tumor cells use to evade detection by T cells.  If approved, durvalumab may compete with Opdivo (nivolumab), which received approval for the treatment of metastatic urothelial cancer on Feb. 2, 2017.

-This investigational anti-PD-L1 mAb is being investigated for its efficacy in treating metastatic Merkel cell carcinoma (MCC) and bladder cancer.  It is being co-developed by Merck KGaA and Pfizer. It has the potential to be the first treatment for MCC, and has received Breakthrough Therapy, Fast Track, and Orphan Drug designations from FDA for this indication. (11). For the bladder cancer indication, avelumab is a potential competitor to Tecentriq (atezolizumab)-although unlike Tecentriq, avelumab is thought to have a dual mechanism of action, and is thought to preserve antibody-dependent cell-mediated cytotoxicity (ADCC) and help white blood cells find and attack tumors (12). Although the medication is also under investigation to treat NSCLC, ovarian cancer, stomach cancer, renal cell carcinoma, and other cancers, the first potential indications that are expected to launch in 2017 are the MCC and bladder cancer indications.

-UCB and Amgen are backing this mAb, which will serve as an alternate therapy to existing osteoporosis treatments Fosmax (alendronate) and Forteo (teriparatide). Romosozumab was developed to inhibit the production of the protein sclerostin and help increase bone mineral density, especially in the spine and hip regions. In Phase III trials, romosozumab reduced the risk of new vertebral fractures in post-menopausal women after 12 months of treatment (13, 14). "We are pleased to see nearly 15 years of sclerostin antibody research reinforced with these Phase III data," said Sean E. Harper, MD, executive vice-president of research and development at Amgen, in a company press release (15). "Romosozumab, with its dual effect as a bone builder and anti-resorptive, has the potential to play a distinct and important role in the treatment of women with postmenopausal osteoporosis at increased risk of fracture” (15).

-Co-developed by GlaxoSmithKline and Johnson & Johnson subsidiary Janssen Biotech, sirukumab is a human anti-interleukin IL-6 mAb for the treatment of rheumatoid arthritis (RA). It is being investigated as a second-line therapy in five different studies for patients who have had an inadequate response to disease-modifying antirheumatic drugs (DMARDs), were intolerant to tumor necrosis factor (TNF) inhibitors, or for those who failed treatment with methotrexate or sulfasalazine.

	The companies are seeking approval for the drug in both prefilled syringes and in an autoinjector, which may give the drug a competitive advantage over other market contenders. Roche/Chugai's Actemra (tocilizumab)‎-the existing first-in-class product that targets the IL-6 receptor in RA-is typically infused in an outpatient office or hospital setting.

	Sirukumab could also compete with investigational candidate sarilumab, as well as with popular TNF inhibitors for RA such as Humira (adalimumab). Clinical trial results comparing sirukumab to Humira suggested sirukumab was more effective at achieving one of the co-primary endpoints-significantly greater improvement in Disease Activity Score (DAS28)-but both drugs performed about the same for the study’s second co-primary endpoint, which was improvement in the signs and symptoms of RA (16).

-Guselkumab is a mAb that targets a particular subunit alpha (p19 subunit) of IL-23. Janssen is developing the therapy for the treatment of plaque psoriasis, which is interesting because Janssen also holds the rights to Stelara (ustekinumab), an older anti-IL-12/23 p40 mAb that could serve as a competitor to guselkumab. Another anti-IL-23 mAb in the pipeline with an indication for plaque psoriasis is Sun Pharma's tildrakizumab, which is still in clinical trials. Recently approved mAbs to treat psoriasis, such as Taltz (ixekizumab) and Cosentyx (secukinumab), might also serve as competitors, although these therapies target the IL-17 cytokine.

	When compared head-to-head with Humira for 16 weeks, guselkumab was able to produce almost complete skin clearance in a significantly higher proportion of patients (17, 18). Humira was administered ten times during the treatment period, whereas guselkumab was only administered three times during the treatment period, which could make guselkumab an attractive alternative to existing therapies. Results from the NAVIGATE study-which evaluated the efficacy of guselkumab for psoriasis patients who had an inadequate response to ustekinumab-will be presented at upcoming scientific meetings.


	1. FDA, “Novel Drug Approvals for 2016,” 

www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugInnovation/ucm483775.htm

, accessed Feb. 1, 2017.
	2. P.S. Yamauchi and J. Bagel, 

 14 (3) 244–253 (March 2015).
	3. Valeant, "FDA Advisory Committee Recommends Approval Of Brodalumab For Treatment Of Moderate-To-Severe Plaque Psoriasis," Press Release, July 19, 2016.
	4. Roche, "U.S. FDA grants Breakthrough Therapy Designation for Roche's investigational Medicine Ocrelizumab in Primary Progressive Multiple Sclerosis," Press Release, Feb. 17, 2016.
	5. Regeneron, "Regeneron and Sanofi Announce Positive Dupilumab Topline Results from Two Phase 3 Trials in Inadequately Controlled Moderate-to-Severe Atopic Dermatitis Patients," Press Release, Apr. 1, 2016.
	6. Regeneron, "Regeneron and Saofi Announce that Dupilumab Has Received FDA Breakthrough Therapy Designation in Atopic Dermatitis," Press Release, Nov. 20, 2016.
	7. Sanofi, "Regeneron and Sanofi Announce Marketing Authorization Application for Dupixent (dupilumab) Accepted for Review by the EMA," Press Release, Dec. 8, 2016.
	8. D. Thaçi et al., 

 387, pp. 40–52 (2016).
	9. E.L. Simpson et al., 

 375, pp. 2335–2348 (Dec. 15, 2016).
	10. AstraZeneca, "US FDA Accepts First Biologics License Application for AstraZeneca’s Durvalumab in Bladder Cancer," Press Release, Dec. 9, 2016.
	11. Pfizer, "FDA Accepts the Biologics License Application for Avelumab for the Treatment of Metastatic Merkel Cell Carcinoma for Priority Review," Press Release, Nov. 29, 2016.
	12. Personal communication, Sally Beatty, Media Relations at Pfizer
	13. Amgen, "Results from Phase 3 FRAME Study of Romosozumab Showed Significant Reductions in Both New Vertebral and Clinical Fractures in Postmenopausal Women with Osteoporosis," Press Release, Sept. 18, 2016.
	14. M.R. McClung et al., 

 370, pp. 412–420 (Jan. 30, 2014).
	15. GlaxoSmithKline, "GSK Announces US Regulatory Submission for Sirukumab in Rheumatoid Arthritis," Press Release, Sept. 23, 2016.
	16. Johnson & Johnson, "New Phase 3 Monotherapy Study of Sirukumab Versus Humira and Sirukumab Data in an Anti-Tnf Refractory Population Reported in the Treatment of Moderately to Severely Active Rheumatoid Arthritis," Press Release, Nov. 16, 2016.
	17. Janssen, "New Phase 3 Data Show Efficacy Versus Placebo and Superiority of Guselkumab Versus Humira in Treatment of Moderate to Severe Plaque Psoriasis," Press Release, Oct. 1, 2016.
	18.

 Editors, "Guselkumab Superior to Humira in Phase III Trial," 

www.biopharminternational.com/guselkumab-superior-humira-phase-iii-trial-0

, accessed Feb. 1, 2017.
	19. J.S. Smolen et al., 

 Published Online First: Jan. 13, 2017, doi: 10.1136/annrheumdis-2016-209831.

EvaluatePharma and BioPharm International highlight the antibody-based therapeutics that may gain United States Regulatory approval in 2017.

Therapeutic Antibodies to Track in 2017, Part I

	On an earnings call on Feb. 6, 2017, Catalent was optimistic about the direction of the pharmaceutical outsourcing industry, saying that its dedicated biologics business was 1% of Catalent's total consolidated sales, but has now grown to 4% of total sales.

	Catalent CEO John R. Chiminski noted that there will be more demand than capacity during the next five years, and the demand will likely be “positioned for the less than 5000L trains,” which is where Catalent is investing most of its capital. He said, “Our ability to lock up customers in advance for them to reserve capacity is going up and it has some of the highest margins, I would say, right now in the business, margin percent.”

	In October 2016, Catalent announced the start of the construction on an extension to the company's Madison, Wisconsin biologics manufacturing facility. The company cited market demand as the catalyst to the expansion. During the call, Chiminski noted that the company's facilities are running near capacity, at an "upwards of 90%." A transformation of the business-with a focus on its biologics business-took executives by surprise, said Chiminiski, who said the company did not fully appreciate how quickly the biologics business would bring the company to almost full capacity.

	An investor asked Catalent executives whether the company would have capacity in the United States should the President institute a border tax or some other tax reform that would seek to bring manufacturing operations back to the US. Chiminiski noted that while the company still has capacity in "several" of its key facilities across the US, he warned that certain tech transfers and requirements to increase capacity could take a few years to implement. In the "highly regulated" pharmaceutical business, changes to manufacturing locations-especially locations that have product registered in multiple countries-could take three to five years after accounting for capacity build, registration, and qualification, he said. And in facilities that already have capacity, it still typically takes a contract development and manufacturing organization (CDMO) two to three years to get drug production up and running after it wins the business from a pharmaceutical company.

	When asked by an investor if Catalent was a net importer or net exporter, Chiminiski said, "For our sites in the United States, we are exporting more in terms of dollars in revenues than we are buying in raw materials or services or any other factors of production from offshore." He also said that the company sources most of it API from domestic suppliers.

	The question of manufacturing onshore or offshore gets complicated, said Chiminiski, because contract manufacturing organizations (CMOs) and CDMOs don't actually own the products with which they work-they are merely providing a service to enhance or alter others' products in the processing chain.

	Added Chiminiski, "That'll be kind of a wrinkle that the policymakers will have to think about. And I'm not exactly sure what the impact on Catalent is there in cases where we're getting API but we're not actually buying it."

	In addition, decisions to move manufacturing to areas with a lower tax jurisdiction are usually based on cash flow, not on the expertise of the labor force, noted Chiminski. Thus, there may be fewer companies to want to invert in the CMO/CDMO industry if the human capability to perform the complex processing operations remains in the US. Plus, unlike some pharmaceutical manufacturers that ship their products overseas to exploit the lower cost of labor and then ship products back, CMO/CDMOs have a different type of business. This aforementioned model is “not a feature of our manufacturing footprint as it exists today,” commented Catalent CFO Matthew Walsh.

On a recent call, Catalent revealed that it has reached more than 90% of its current capacity and discussed how tax policy changes could affect the outsourcing industry.

Catalent Predicts More Demand than Capacity in the Next Five Years

	Shire ViroPharma’s filing of 43 documents and three lawsuits against FDA prevented the agency from approving a generic version of Vancocin, a drug to treat 

-associated diarrhea, the Federal Trade Association (FTC) alleged on Feb. 7, 2017. This tactic of “sham petitioning,” as the FTC called it, spanned from 2006 to 2012 and successfully prevented the approval of a competitor to Vancocin. The block of Vancocin’s approval cost patients hundreds of millions of dollars, the FTC wrote in its release. FTC alleges that ViroPharma took advantage of the fact that FDA cannot approve any generic applications until it resolves pending citizen petition filings.

	The serial petitioning by ViroPharma occurred in 2006 following a FDA recommendation that generic equivalents of Vancocin be tested for bioequivalency in test tube dissolution studies, rather than in human subjects. FTC estimates that it could have approved a generic equivalent of Vancocin as early as July 2010, but that the aggressive tactics from ViroPharma kept the agency from approving a generic to Vancocin until August 2012. Generic versions of the drug from Akorn, Strides Inc., and Watson Laboratories were eventually approved in April 2012.

	ViroPharma, as a result, was able to maintain its monopoly on the 

 market for an extended period of time. According to the FTC complaint, the filings were the most that any pharmaceutical firm has ever made to FDA concerning a single medication.

	Even after 16 experts unanimously decided the filings from ViroPharma had no merit and did not raise any valid scientific issues, the company continued its aggressive tactics, “which ViroPharma understood it needed to have any chance of persuading the FDA of its positions,” according to the complaint. The filings mostly challenged FDA’s bioequivalence guidance.

	In addition, ViroPharma didn’t even develop the drug initially. It acquired the drug from Eli Lilly in 2004 and raised the price steadily until 2011. During 2004–2011, Vancocin was ViroPharma’s main source of revenue-sales for the product grew from approximately $40 million in 2003 to almost $300 million by 2011. This all-too-familiar pricing model is especially common with older medications that are no longer protected by patents (such as was the case with Turing Pharmaceuticals and Daraprim).

	In related news, Pfizer recently released results from its Phase II trial for a 

 vaccine, which showed the vaccine successfully increased vaccine-elicited neutralizing antibodies to two toxins produced by the bacteria. The vaccine 

 a Fast Track designation from FDA in 2014.

Aggressive petitioning by ViroPharma kept a generic equivalent to Vancocin off the market for more than two years.

FTC: Shire ViroPharma Filed Bogus Petitions to Delay C. Diff Generic

	Amgen announced on Feb. 2, 2017 that the company’s FOURIER trial met its endpoints and that treatment with Repatha successfully reduced the risk of heart attack and stroke in patients whose low density lipoprotein cholesterol (LDL or LDL-C) was inadequately controlled with statins. Detailed results from the Repatha FOURIER outcomes trial and the related EBBINGHAUS trial will be presented at the American College of Cardiology meeting on March 17–18, 2017.

	In the prior OSLER-1 and OSLER-2 trials for Repatha, there was evidence of an increase in adverse neurocognitive events. Approximately 1900 patients enrolled in the new FOURIER study were also enrolled in the EBBINGHAUS study-which measured memory and psychomotor speed-to assess the overall neurocognitive function of patients who were treated with Repatha.

	Amgen banking on broader access and improved uptake

	This new, protective indication could serve to make Repatha more attractive to payers in the long run and could allow the product to enjoy broader access. Currently, 75% of Repatha prescriptions 

 by payers, largely because of its $14,000 price tag and its narrow indication for those with with heterozygous familial hypercholesterolemia (HeFH) or clinical atherosclerotic cardiovascular disease (CVD) who require additional lowering of low density lipoprotein cholesterol (LDL-C). But now that the drug has demonstrated a more significant clinical benefit in the prevention of cardiovascular events, it should be harder for payers to reject reimbursement claims. Amgen’s Anthony Hooper, executive vice-president of global commercial operations, recently said in fourth-quarter earnings call that the company’s focus remains on helping all payers improve access to Repatha. “The utilization management criteria that they have at the moment is beyond the label and we work every day to improve upon that,” noted Hooper. “We look forward to seeing the payer response now that we have the outcomes data. But of course, we won't be able to promote that until it's in the label.”

	The new efficacy data, coupled with a monopoly position in the market due to a 

 prohibiting Sanofi and Regeneron from making and selling Repatha's competitor, Praluent (alirocumab), could significantly increase Amgen's revenues in 2017 and beyond. In fact, David Meline, Amgen’s CFO and executive vice-president, said in a fourth-quarter company call that as a result of the new positive cardiovascular data and the outcome of Repatha's legal case (and consequently, the switch from Praluent to Repatha for a majority of current Praluent patients), the company's guidance ranges "are wider" than they have been in preceding years.

	In light of the aforementioned circumstances, it appears that a 

-that PCSK9 drugs "will likely be the highest selling class of medications in history"-was right on the money.

According to results from the FOURIER trial, Repatha significantly reduced the risk of cardiovascular events and death in patients with atherosclerotic cardiovascular disease.