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

Randi Hernandez

	Pfizer executives were not among the pharma representatives who met with Trump yesterday to discuss various issues affecting the industry, a circumstance that Pfizer attributed to a schedule conflict with its quarterly earnings call. Despite the company’s absence from the meeting, Pfizer’s CEO Ian C. Read commented on some of Trump’s policy suggestions, and also discussed sales trends and projections for Pfizer’s R&D pipeline.

	Bringing manufacturing jobs back to the United States would imply a change to the corporate tax code, and perhaps a repatriation initiative, said Read. He noted a major component of getting manufacturing back to America “falls squarely inside of getting a tax reform which allows us to reinvest in the United States and create jobs.” Read continued, “we can be a very positive part of the story of creating jobs in the United States if we get the tax reform," a point that he reiterated later during the call.

	Pfizer has benefitted from previous repatriation efforts. In 2004, as a result of the American Jobs Creation Act, Pfizer was among the top five companies that were responsible for $88 billion in repatriations, according to estimates from the 

. Pfizer received $37 billion of the repatriation money as a result of the initiative.

	In 2005 and 2006, however, Pfizer eliminated 10,000 jobs. Thus, ironically, repatriation and the “job creation” push resulted in fewer company positions.

	In a note to investors, Marc Shoenebaum of Evercore ISI said that his company had spoken with Pfizer about potential cash repatriation, and Pfizer said it could potentially increase US cash from about $10 billion to roughly $60–70 billion by repatriating approximately $14 billion in cash from outside the US and raising about $40 billion in additional debt, wrote Shoenebaum. He also noted that Pfizer executives warned that repatriation might contribute to rises in asset pricing.

	Read appeared to support Trump’s decision to reduce FDA regulations, saying it would help contribute to lower drug prices. In the call, Read did not elucidate how the cost of drug development (which has historically factored into drug pricing decisions) would change as a result of fewer regulations. Read also seemed to focus on the approval of generics, rather than on branded medications that have no or few competitors.

	Trump is “going to cut up to 80% to help streamline the approval process. That will help with drug prices, because it'll induce more competition,” said Read. “We have been advocating for a long time to speed up the approval of generics and remove the barriers to their approval, because that will help with drug prices.”

	Read said he interpreted some of Trump's remarks on regulations to be related to how insurance companies determine the cost of drugs for patients. "Cost to patients is driven by the fact that the out-of-pocket expense on average for a patient to visit a hospital is 3%, but on his drug bill, it's 15%. So we'd like to see regulations that would allow that unfair playing field to be squared up."

	To ensure that patients have affordable drugs, new regulations or changes to existing regulations may be necessary, noted Read during the call. Specifically, he mentioned changing regulations "to allow value-based contracting between the industry and the health system . . . We have a regulation that was created for fee-for-service, and now we need regulations in a new world of value-based pricing." But an executive order issued on Jan. 30, 2017 requires federal agencies to remove two regulations with the introduction of any new regulation-so new regulations on value-based pricing, as Read suggested, may sacrifice some older regulations that are already in place.

	The sale of the vaccine Prevnar 13 was also an important focus of discussion, as Prevnar 13 contributed approximately $6.2 billion in worldwide sales in 2015. Read said that because the company has already “vaccinated approximately 50%” of those over age 65, Read expects to see a decline in sales for the adult population. "In the US, Prevnar 13 declined 33% due to a decrease in revenues for the adult indication after the high initial capture rate of the eligible population following its successful fourth quarter of 2014 launch, which resulted in a smaller remaining catch-up opportunity compared to the prior-year quarter and the unfavorable impact from the timing of government purchases to the pediatric indication.”

	According to Pfizer spokesperson Sally Beatty, the government purchasing portion of Read’s comment refers to the fact that the timing of vaccine purchasing decisions is not predictable; the government “has its own rhythm” when it comes to purchasing vaccines, according to Beatty, and this timing negatively affected the sales of Prevnar 13 in 2016. Sales of the vaccine in 2017 are expected to be flat or slightly down, but may be offset by sales to pediatric patients.

	Pfizer expects a decision in 2017 on its investigational PD-L1 candidate, avelumab, for the treatment of Merkel cell carcinoma.  Avelumab, the company said, will be important as a monotherapy, but its senior management team believes that its true value will be seen in combination therapies, where it might be coupled with targeted agents such as Inlyta, or with antibody-drug conjugates, vaccines, and other immuno-oncology agents in Pfizer's pipeline. The company reports having 14 biosimilar molecules in development and expects “readouts” on its bavituximab and filgrastim products in 2017.

Articles

A change in the tax code could help the company create more jobs in the United States, while fewer FDA regulations could help reduce drug prices, according to Pfizer CEO Ian Read.

Pfizer Reacts to Trump’s Comments and Discusses Pipeline in Its Q4 Earnings Call

	In a short, televised statement on Jan. 31, 2017, President Donald Trump 

spoke with leading biopharma company executives

 about inefficiencies at the FDA, pharmaceutical manufacturing jobs in the United States and abroad, and “foreign price controls on drugs.” The wide-ranging statement, however, did not provide insight about how the administration plans to fix the problems identified including patient access to experimental drugs, “astronomical” pricing for drugs in the US market, faster drug approvals, foreign price controls, and offshore manufacturing. Trump’s remarks came prior to a meeting with Celgene CEO Bob Hugin, Merck CEO Ken Frazier, President and CEO David Ricks from Eli Lilly, Novartis CEO Joe Jimenez, and members of the trade group PhRMA.

	Trump said the government must "streamline the process" of drug approvals and make the process "much faster" and referenced how terminally ill patients should have access drugs in that are still in development stages. Expediting approvals will be a major task for FDA, which currently has hundreds of vacant positions and faces a federal hiring freeze initiated by the Trump administration last week. In addition, an executive order issued on Jan. 30, 2017 requires federal agencies to remove two regulations with the introduction of any new regulation. According to 

, Trump said at least 75% of all regulations will be eliminated.

	It is "unfair what other countries are doing to us," said Trump in the statement, and that foreign companies must "pay their fair share" for US-manufactured drugs so that US companies have more money to innovate. He also mentioned "ending global freeloading", saying that “foreign price controls reduce the resources of drug companies to finance R&D.”

	Trump urged the pharma executives, "you have to get your companies back here," suggesting that biopharma should return operations to the US. Prior to winning the Presidency, Trump 

	PhRMA President and CEO Stephen Ubl said in a statement that the meeting was positive and that reforming the tax code, moving towards a value-based drug pricing system, removing outdated regulations, and creating better trade agreements would benefit the industry. “We believe if these policies are enacted, it will translate to up to 350,000 new jobs over the next 10 years as a result of growth in the biopharmaceutical industry,” Ubl said.

Trump met with pharma manufacturers and makes a statement focused on domestic manufacturing, FDA approvals, and drug pricing.

President Trump Meets with Pharma Manufacturers

	In Danaher’s life-sciences sector, reported revenue was up 6% and core revenue grew 4% during the fourth quarter of 2016. Reported operating profit margin increased to 16.8%, and reported revenue for 2016 was up 17% from 2015.

	Danaher executives said operational improvements seen at Pall were a growth driver for the company. Growth in the single-use business at Pall, however, was offset by declines in its process technologies business. Nonetheless, the company managed to release 35 new products in 2016, which the team said got to market 25% faster than products in 2015.

	The Danaher team also mentioned that 2016 brought the release of the SCIEX X500B mass spectrometer for the characterization of biologics and the close of the acquisition of Phenomenex, a chromatography consumables business.

Operational improvements at Pall contributed to the overall growth in the Danaher life-sciences sector.

Danaher Reports Revenue Increases of 17% in 2016

	Chimeric antigen receptor T cells (CAR-T) are hot in the biotech world, and the science community has been tinkering with the constructs to improve their efficacy in real-world settings. One of these parameters is manufacturability; allogeneic cells are ideal for large-scale manufacturing and to reduce some of the heterogeneity that is associated with autologous T-cell therapies.

 recently spoke to Alexandre Juillerat, PhD, innovation senior scientist at Cellectis, to find out how Cellectis’ CAR construct differs from others in development and how the company’s novel approach to T-cell architecture allows it to be eligible for future improvements in safety and/or efficacy. For background information on the new CAR-T, please read 

“Cellectis Describes Novel CAR-T Design in New Paper.”

 The extensive expansion of T-cell therapies carries the risk of cell senescence. How would Cellectis overcome this challenge in the manufacture of its allogeneic cells?
	

 The cells we are using are from healthy donors. They are not exhausted because of chemotherapy, for example.

 The UCART123 investigational agent is said to be the first investigational new drug (IND) filing for a gene-edited T-cell product in the US. What about worldwide? Are there others that are first elsewhere
	

 UCART123 is the first IND filing for a gene-edited CART-cell product in the US. Sangamo filed an IND for clinical trials in HIV/AIDS. Their product, a gene-edited T-cell product, is currently being tested in Phase I/II in the US. In addition to the IND filed for UCART123, we filed CTAs [clinical trial authorization] (equivalent of an IND in the UK) for UCART19. To our knowledge, there is no other IND filed for gene-edited T-cell product. 

Editor’s note: There may be an IND from Sangamo on the horizon. In a 2011 

, Sangamo said the company’s focus is the development of zinc finger DNA-binding protein (ZFP) Therapeutics. Their lead ZFP Therapeutic, SB-728-T, is a ZFN-modified autologous T-cell product for the treatment of HIV/AIDS. In a January 11, 2017 

, Sangamo wrote, “We are also moving quickly to advance additional ZFP Therapeutic programs into the clinic with the target of filing six more IND applications over the next twelve months."

Would the oxygen-specific construct in your recent study be considered a "bispecific" construct? Why or why not?
	

 'Bispecific' T-cells are mainly described as engineered T-cells that can recognize two different antigens to allow improved discrimination between healthy tissues and tumors. However, such approaches may suffer from the difficulty to select combinations of suitable target antigens (e.g., avoiding the so-called antigen escape). In our recent paper, we replaced the requirement of finding a second antigen by focusing on the tumor microenvironment. By analogy to other recent synthetic biology strategies based on the use of exogenous small molecule drugs to control CAR T-cell, our oxygen-sensitive system would rather be considered a dual-input system (one antigen-based input and one microenvironment-based input). It should also be noted that our approach can be combined to 'bispecific' strategies to create additional layers of safety.

 How many subdomains were added to the CAR constructs, and what are they? (i.e., were there two inputs on one domain)?
	

 On the construct (the chimeric antigen receptor), we have developed contains four functional subdomains: an antigen-targeting domain, a T-cell activation domain, a T-cell co-stimulation domain, and an oxygen-sensitive domain. One of the innovations of our CAR resides in the fact that these domains are spread between three chains of a multichain receptor instead of being piled one after the other in more classical CAR constructs. Such a novel approach allows more freedom in the addition of new functionalities. We also combined the two inputs (antigen-recognition and microenvironment-sensing) on the same chain to strengthen the requirement of having the two functional inputs.

Alexandre Juillerat, PhD, innovation senior scientist at Cellectis, discusses novel construct UCART123, an investigational agent that is on deck to be the first gene-edited T-cell product in the United States.

Honing in on the Tumor Microenvironment

	Humira (adalimumab) will still be protected from market competition until 2022, said Richard Gonzalez, chairman and CEO of AbbVie, in a recent fourth-quarter investor call. The drug drove 16% global operational growth in 2016, including United States growth of 24% and international operational growth of 4.3%.

	Gonzalez compared Humira to other products that have approved biosimilars on the market outside of the US, such as Remicade (infliximab) and Enbrel (etanercept), which each have approximately 3%–5% of the overall market. Gonzalez said he is watching the erosion curve carefully, but that Humira's competitors should have uptake similar to what the market has seen with Remicade and Enbrel biosimilars.

	Supply chain model for biologics should help biologics retain market share

	Product substitution at the pharmacy level is not really a threat for biologics like Humira, said Gonzalez, unless competing programs are able to achieve interchangeability.

	He said, "very little or almost none of biologics go through retail pharmacy, they go through and are dispensed through specialty pharmacy where your formulary position is really what dictates what product is dispensed, not the individual pharmacy. So, I don’t think it [interchangeability] fundamentally changes that part of the strategy."

	One investor asked if the company had flexibility to move its manufacturing operations for Humira to the US should there be some type of formal mandate from the current President of the United States or in the event that "there is a tax paradigm that favors the US." Gonzalez said this should not really be an issue, as Humira is largely manufactured in Massachusetts and Puerto Rico. He said any decisions to move the supply chain could ultimately depend on whether Puerto Rico would be considered a part of the US by the powers that be (it is a territory of the US).

Despite the threat of competition, both from biosimilars to Humira and new therapies that work through other mechanisms of action, AbbVie says Humira is still number one.

AbbVie: Despite Competition, Humira Still the Number-One Prescribed Biologic

	Celgene will further bolster its capabilities in immunology and autoimmune disorders with the acquisition of the biotechnology company Delinia, a move Celgene announced on Jan. 26, 2017. With the company comes the ownership of DEL106, a novel IL-2 mutein Fc fusion protein that is designed to upregulate regulatory T cells (Tregs).

	Tregs maintain tolerance to self-antigens and are instrumental in the prevention of autoimmune diseases. Thus, Tregs are immunosuppressive and work to downregulate induction and proliferation of effector T cells. The cytokine IL-2 normally activates effector cells, but also drives expansion of Tregs to regulate the effector cells.

	Celgene will pay Delinia an initial payment of $300 million, with additional payments of up to $475 million upon the development, regulatory, and commercial advances related to DEL106. DEL-106 is expected to start clinical trials in 2018.

The company will gain the rights to a mutein that is believed to help maintain immune system homeostasis.