Alnylam Pharmaceuticals' Approach For Transitioning From R&D To Commercial Mode

By Rob Wright, Chief Editor, Life Science Leader
Follow Me On Twitter @RfwrightLSL

Three days before the 2015 Christmas holiday, Alnylam Pharmaceuticals and the Norton, MA, city council decided to exchange presents. The council signed off on a 13-year tax incentive (i.e., a $7 million tax break) in exchange for Alnylam agreeing to build a proposed $100 million facility that will eventually employ up to 220 workers. Upon seeing the news, Life Science Leader reached out to Alnylam executives Barry Greene, president and COO, and Al Boyle, SVP of technical operations. Our goal was to not only learn the rationale behind the plant site selection, but gain insight for how the company is preparing the market to receive RNA interference (RNAi); a biological process in which RNA molecules inhibit gene expression by turning genes within cells either on or off. Should Alnylam’s lead compound, patisiran, have positive Phase 3 results for the treatment of Transthyretin (TTR)-mediated amyloidosis (ATTR), an inherited, progressively debilitating, and often fatal disease caused by mutations in the TTR gene, the company would not only need to have a manufacturing facility capable of producing enough commercial supply, but prepare the market for therapeutic with a novel mechanism of action.

Life Science Leader (LSL): Can you elaborate on the challenges a company faces in building a commercial operation at-risk and your approach for managing?

Greene: “There are many activities that need to be done two, even three years before launch on the commercial, medical, and manufacturing sides. Because we believe that we have a reproducible and modular platform to produce many drugs, we’re not only counting on our lead drug, patisiran, but are being thoughtful about the capabilities and the kind of company we want to build in order to support multiple products. We have a goal of having three drugs approved that we will commercialize in the U.S. and Western Europe by 2020 with Sanofi commercializing in the rest of the world. We’re being thoughtful about the people, the technology, and the processes we need to put in place to prepare not only for our first launch, but launches thereafter. When you combine the nature of our platform with the fact that we have highly visible data in early clinical development for genetically valid targets that we are pursuing, we believe we are assuming much less risk in our Phase 3s. While we are being balanced about our spend, we are also being diligent about ensuring that the strategies, plans, and activities that will make us successful are being put in place.”

LSL: How do you go about shifting Alnylam’s focus from an R&D organization to one involved in selecting a site and building a plant?

Boyle: “With the number of products we have in the clinic, from a technical operations perspective, a lot of the infrastructure that you need already exists in order to make and ship compliant product. Now it is about scale. Once you get to a tipping point, assuring that you can deliver sufficient quantities at a commercial scale requires investment in the plant of the future. While our Alnylam 2020 plan (long-term guidance) is important, we need to look well beyond that point in time. With the RNAi approach, we believe there to be a high degree of success for our pipeline. We’ve looked at the site, we’ve looked at the location, and we’ve also looked at how we’re going to design it and what we’re going to build in the near term versus what we can add to the facility later. Transforming the company from R&D to commercial requires anticipating the steps you’re going to take. It’s not just being able to add on to a facility in a modular fashion, because when you do things like that you can interrupt what you are already doing even after you’ve built the first piece. We look at that not only from a manufacturing facility, but all things we do to support the operations.

• “We managed the site selection process via a small internal team. Establishing an internal team to work with an external team starts with defining the roles you need and when you need them. Further, we established a hiring plan that aligns with your build plan, but also accounts for the end user being involved early enough in the process so they can influence the end product to meet needs and expectations. We identified potential sites based on established criteria. While our preference was for greenfield sites, brownfields sites were evaluated as well. We looked at 150 locations around the world and narrowed it down to a list of fewer than 10. Some of the key drivers included access to high quality talent, proximity to Cambridge, and a local government wanting and willing to support biopharmaceutical manufacturing. As a growing and emerging company at a very important stage of development, when we managed risk versus benefit, control and oversight became key deciding factors. With regard to plant design, the process for selecting an architect and design firm is similar in principal to selecting any vendor. A key is clearly establishing what you want the vendor to deliver. It is also important to be clear on company expectations of the firm and getting to know their style to ensure a sound working relationship. Plant design plays an important role in site selection. Facility design must consider known near term and anticipated long-term product needs. The design must be configured to deliver on the known and be able to evolve to the anticipated once those needs are realized while continuing to manufacture product and meet the needs of our patients. The plant will use a combination of stainless steel and disposable technology. For us the keys are to robustly assess risks and benefits, set high expectations for quality regardless of technology and establish appropriate redundancy and risk mitigation actions. These principals will allow for both technologies to support business needs. Some of the best insight gained from the site-selection experience is that many municipalities and regional governments are collaborating to attract businesses and often have compiled and aggregated regional data that can be very informative and reduce internal efforts as well as contracted resources. As you engage local and state officials, be sure to share your objectives and ideas transparently. Because it is their job to help bring jobs to their constituents, they will know much more than you about all of the incentives, both existing and future. This information can prove very influential in your decision making process.”

LSL: What should a CEO of a biopharmaceutical company focus on when building a commercial engine?

Greene: “As you’re developing a molecule, a drug, or a new technology, first, always start with the end in mind.  What is it you want to try to become? Different people have different strategies. For Alnylam, our end goal is be a fully integrated commercial company, selling our own products in at least the United States and Western Europe. Second, be product-focused. Whenever a new technology is being developed you have to have a product focus that meets whatever the big unmet medical need is. What diseases can you go after? What opportunities does your product or technology have that can be transformational for patients? Incremental improvements are not going to get approved or paid for these days. When you understand those things (e.g., the opportunity for your product or technology, unmet need, etc.) and put the plans in place, you have to be thinking about the patient being able to access your product, as well as your company’s ability to get reimbursed.”

Boyle: “When you have a transformative therapy, you have an obligation to be able to deliver to the patient. Having a great solution and not being able to deliver is unacceptable. As you’re building your capabilities you have to look at strategy, because we all know a company can’t afford to build three plants in year one. It’s a very common strategy to have partnerships. But it’s also very important as you’re developing those partnerships to look at redundancy in order to be able to ultimately deliver the product or technology to the patient. While you know you can’t do it all by yourself, especially early on, at the end of the day your company is responsible and accountable for supply.”

LSL: What are some of those key relationships?

Boyle: “Well, we know about CMOs (contract manufacturing organizations), the likes of which are many. But there are also university relationships. There are a lot of folks with experience that are on the back sides of their careers that can help guide you. There’s a lot of knowledge and creative ways to develop relationships in order to get a product made. Once you get to the space where you have to deliver to the clinic, you have to remember – and this is a piece I think a lot of early entrepreneurs don’t realize or tend to forget – the compliance aspect with the regulatory agency. We think about clinical trial design. But we also have to remember the compliance of making the product and having strong partnerships with people who can enable you to go from early phase to late phase and bring the quality with it along the way.”

Greene: “At the end of the day, it’s all about patients and the impact you have on their disease, irrespective of modality, technology, or otherwise. When you have a kid that’s bleeding frequently and doesn’t have access to their veins because of all the sticking you have to do with diseases like Hemophilia, other alternatives are a blessing. There’s definitely a market pull when you have unmet need, bad diseases, and an opportunity to be transformative. We have to make sure that we understand the patient, as well as the caregiver’s perspective, and the market dynamic in terms of payers and providers, and be able to educate and communicate.”

LSL: How are you preparing so as to not fail the patient on delivery?

Boyle:  “It’s about redundancy and inventory. Those two elements are the foundations of our strategy. The facility that we already have will be an element to help build inventory to support a launch. From there you need to look at your demand and balance what you’re going to carry with inventory versus shelf life. That’s how you work your supply chain. You do it with every element. There are multiple nodes in the manufacturing process (e.g., drug product, drug substance). Any strong and robust supply chain has elements of redundancy and inventory management at every aspect. We feel very comfortable that we’ve developed an enabling strategy for what lies ahead. We’ll have our own manufacturing facilities and will leverage third party manufacturing facilities to build inventory and redundancy to ensure delivery of product to patients..”

LSL: How are you preparing the market for RNAi?

Greene: “First, we have to educate people about the disease itself. If someone with familial amyloidotic polyneuropathy (FAP) shows up at the family doctor’s office, the physician may or may not know the disease. We have to do a lot of education from the disease thought leaders (i.e., neurologists), to the next level of providers (i.e., family physicians). Our tipping point in doing that was when we saw the 18-month data on the open label extension study. Instead of neurological progression at about 24 points, these folks were stable with about a 1.7 point increase. In fact, we saw regrowth of nerve fibers. That data gave us the courage to start scaling up, educating, and building towards inventory and other things. We also got anecdotes from patients about survival, feel, and function — the kinds of things agencies look at. Instead of talking theoretically, we can actually point to real data from an education perspective. Along the way, we are explaining what patisiran is, what RNAi therapeutics are, and making sure people understand that in the case of FAP, what we’re able to do is take the pathogenic protein causing the disease and greatly decrease its circulation and hopefully making people better. For our hemophilia program, very early in Phase 1, in people with severe hemophilia, when you decrease the target, antithrombin, you increase thrombin. When we gave these people fitusiran they bled much less. That gave us the confidence to announce our Phase 3 this year, as well as to begin educating the hematology community about the potential positive effects of how and why our drugs work, while also highlighting the potential safety risks. In addition, we are also working closely with the clinical site investigators. Back to FAP, we had about 50 sites for patisiran up and running around the world. One of the unique things we did is was to make sure we had people capable of educating patients and investigators in the local language. Further, while we are willing to work with existing patient associations, we are also open to helping create foundations in areas where they are absent. For example, in Mexico we sponsored a clinical investigator patient seminar that was attended by nearly 60 patients. However, a patient advocacy organization did not yet exist. Yet, as a result of such strong attendance, thanks to the help of these investigators, for the first time ever a patient advocacy society was formed in the area. Another program we developed in the fall of 2014 is called Alnylam Assist. It provides free genetic testing for physicians and patients if they have symptoms related to either FAP or the cardiomyopathy phenotype. Finally, we also did work with payers and providers to make sure they understood the diseases and got buy-in for some of our Phase 3 end points. In this way, we could not only address the regulatory end points, but real world end points as well (e.g., grip strength, caring for themselves, walking). In summary, preparing the market involves payer, provider and patient education, key opinion leader and investigator development, and internal capabilities to continue to do that on an ever greater scale. Many elements required for producing commercial product are established when drug candidates enter clinical trials, such as cGMP manufacturing capability to produce product, quality systems to ensure safety and compliance, supply planning to manage inventory and assure patients receive product, and a logistics network to deliver product when needed in the clinic. A key in transitioning from R&D to commercial is the scale of these operations to manage increased volume of product and broader geographic scope. In addition, the infrastructure required to manage the lifecycle of a product must be established. All of these activities are currently ongoing and we are positioned well to ensure readiness upon approval of patisiran.”