What changed in this filing

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Item 1A. Risk Factors

2020-08-06 compared with 2020-05-06 · 152 added, 118 removed, 960 unchanged (22% of the section changed)

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In December 2019, a novel strain of coronavirus, or COVID-19, was reported to have surfaced and it has now reached multiple regions, countries and cities, including Cambridge, Massachusetts where our primary office and laboratory space is located, and all countries in which we have offices.

The COVID-19 pandemic is evolving, and to date has led to the implementation of various responses, including government-imposed quarantines, travel restrictions and other public health safety measures.

The extent to which COVID-19 impacts our operations or those of our third-party partners will depend on future developments, which are highly uncertain and cannot be predicted with confidence, including the scope, severity and duration of such pandemic, the actions taken to contain the pandemic or mitigate its impact, and the direct and indirect economic effects of the pandemic and containment measures, among others.

The rapid development and fluidity of this situation precludes any prediction as to the full adverse impact of the COVID-19 pandemic.

The COVID-19 pandemic continues to evolve, and to date has led to the implementation of various responses, including government-imposed quarantines, travel restrictions and other public health safety measures.

Certain jurisdictions have begun re-opening only to return to restrictions in the face of increases in new COVID-19 cases.

COVID-19 has and will likely continue to impact our operations and those of our third-party partners and the ultimate impact on our business and financial results remains uncertain and cannot be predicted with confidence, and will depend on many factors, including the scope, severity and duration of the pandemic, the actions taken to contain the pandemic or mitigate its impact, and the direct and indirect economic effects of the pandemic and containment measures, among others.

The rapid development and continued fluidity of this situation precludes any prediction as to the full adverse impact of the COVID-19 pandemic.

Nevertheless, the COVID-19 pandemic may adversely affect our business, financial condition and results of operations.

We also suspended non-essential travel worldwide for our employees and may take further measures as the pandemic continues.

In addition, our customer-facing employees in most markets have moved to virtual interactions with healthcare providers, administrators, patients, payers, regulators and other government employees.

In response to the spread of COVID-19, we have taken temporary precautionary measures intended to help minimize the risk of the virus to our employees and their families, including implementing a global work from home policy for nearly all employees who are able to perform their duties remotely, and have generally restricted on-site staff to only those personnel and contractors who perform activities that need to be completed on-site, limited the number of staff in any given laboratory, manufacturing facility or other facility and implemented safety practices and procedures for those individuals who are required to work in our facilities, including but not limited to mandatory health screening, the use of face coverings, physical distancing requirements and increased cleaning protocols.

We also suspended non-essential business travel for our employees and may take further measures as the pandemic continues.

In addition, our customer-facing employees in most markets moved and could again need to move to virtual interactions with healthcare providers, administrators, patients, payers, regulators and other government employees.

At this time, we cannot predict when certain restrictions that are in place to protect our employees can be reduced or will no longer be needed.

The effects of government-imposed quarantines and our work-from-home policies may negatively impact productivity, or disrupt, delay, or otherwise adversely impact our business.

In addition, this could increase our cyber security risk, create data accessibility concerns, and make us more susceptible to communication disruptions, any of which could adversely impact our business operations.

As a result of the COVID-19 outbreak, we may experience disruptions that could severely impact our business and operations, including our ability to successfully commercialize our approved products, ONPATTRO and GIVLAARI, and due to the current pandemic, we may not be able to meet expectations with respect to commercial sales.

For example, due to the impact of the COVID-19 pandemic, product revenues for ONPATTRO could potentially decrease by about 10% in the second quarter of 2020, and our ONPATTRO product revenues could be less than originally forecast for 2020.

Compliance with governmental measures imposed in response to COVID-19 has caused and will continue to cause us to incur additional costs, and any inability to comply with such measures can subject us to restrictions on our business activities, fines, and other penalties, any of which can adversely affect our business.

In addition, the increase in certain of our employees working remotely has amplified certain risks to our business, including increased demand on our information technology resources and systems, increased phishing and other cybersecurity attacks, and any failure to effectively manage these risks, including to timely identify and appropriately respond to any cyberattacks, could adversely impact our business operations.

As a result of the COVID-19 pandemic, we may experience disruptions that could severely impact our business and operations, including our ability to successfully commercialize our approved products, ONPATTRO and GIVLAARI, and due to the current pandemic, we may not be able to meet expectations with respect to commercial sales.

For example, due to the impact of the COVID-19 pandemic, product revenues for ONPATTRO could be less than originally forecast for 2020.

In addition, we may also experience decreased patient demand for our approved products if current or potential patients decide to delay treatment as a result of the COVID-19 pandemic.

For example, in the second quarter of 2020, we experienced a decrease in patient demand in the U.S.

due to reduced adherence as some patients skipped doses or experienced dose delays while moving to new sites of care, and additionally experienced reduced requests for genetic testing through our third party genetic testing program resulting in delays in diagnoses of the rare diseases our medicines are approved to treat, which could have an adverse effect on revenues in future periods.

In addition, business interruptions from the current or future pandemics, including staffing shortages, production slowdowns and disruptions in delivery systems, may also adversely impact the third parties we or our partners rely on in the U.S.

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Additionally, timely completion of preclinical activities and initiation of planned clinical trials is dependent upon the availability of, for example, preclinical and clinical trial sites, researchers and investigators, patients or healthy volunteer subjects available for recruitment and enrollment, and regulatory agency personnel, which may be adversely affected by global health matters, such as the COVID-19 pandemic.

We are conducting and plan to continue to conduct preclinical activities and clinical trials for our drug product candidates in geographies which have been and continue to be affected by COVID-19, and believe that the COVID-19 pandemic will have an impact on various aspects of our ongoing clinical trials and on the clinical and preclinical trials we expected to initiate in 2020.

We are conducting and plan to continue to conduct preclinical activities and clinical trials for our drug product candidates in geographies which have been and continue to be affected by COVID-19, and believe that the COVID-19 pandemic will have an impact on various aspects of our ongoing clinical trials and on the clinical trials and preclinical studies we expected to initiate in 2020.

For example, certain trial sites in some of our ongoing clinical trials have been restricted temporarily by the institutions where they are located from scheduling patient visits or permitting onsite monitoring and in some of our ongoing trials, delayed or missed doses of study drug have been reported.

In addition, in May 2020, we announced that due to the impact of the COVID-19 pandemic, enrollment delays in our APOLLO-B Phase 3 study of patisiran for the treatment of ATTR amyloidosis with cardiomyopathy will result in a shift in the enrollment completion date from late 2020 into 2021.

We also announced that we plan to shift the filing of our IND for ALN-LEC into 2021 in order to focus on our COVID-19 investigational RNAi therapeutic program.

Health regulatory agencies globally may also experience disruptions in their operations as a result of the COVID-19 pandemic.

The FDA and comparable foreign regulatory agencies may have slower response times or be under-resourced, which could significantly delay the FDA or EMA’s ability to timely review and process any submissions we or our partners have filed or may file.

While the FDA recently announced plans to resume domestic facility inspections following the March 2020 suspension of most foreign and domestic facility inspections, the FDA and comparable foreign regulatory agencies may have slower response times or be under-resourced, which could significantly delay the FDA or EMA’s ability to timely review and process any submissions we or our partners have filed or may file.

For example, any delay by the FDA or EMA could impact the regulatory review of our NDA and MAA submissions for lumasiran or the NDA and MAA submissions for inclisiran, which is being advanced by our partner, MDCO, which could materially and adversely affect our business.

Some factors from the COVID-19 outbreak that may delay or otherwise adversely affect enrollment in and the conduct of the clinical trials of our product candidates, as well as adversely impact our business generally, include:

Some factors from the COVID-19 pandemic that may delay or otherwise adversely affect enrollment in and the conduct of the clinical trials of our product candidates, as well as adversely impact our business generally, include:

• the ongoing diversion of healthcare resources away from the conduct of clinical trials to focus on pandemic concerns, including the availability of necessary materials and the attention of physicians serving as our clinical trial investigators, hospitals serving as our clinical trial sites and hospital staff supporting the conduct of our clinical trials;

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The global pandemic of COVID-19 continues to rapidly evolve.

The ultimate impact of the recent COVID-19 pandemic is highly uncertain and subject to change.

The ultimate impact of the COVID-19 pandemic is highly uncertain and subject to change.

We do not yet know the full extent of potential delays or impacts on our business, our commercial results, clinical trials, healthcare systems or the global economy as a whole.

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To date, we have launched ONPATTRO in the U.S., Japan, Canada, Brazil and in several countries in Europe.

In addition, in November 2019, the FDA approved our second product, GIVLAARI, which was also approved by the EMA in March 2020.

While we have commercially launched ONPATTRO and GIVLAARI, we have limited experience as a commercial company and there is limited information about our ability to successfully overcome many of the risks and uncertainties encountered by companies commercializing products in the biopharmaceutical industry.

In addition, in November 2019, the FDA approved our second product, GIVLAARI, which was also approved by the EMA in March 2020 and Brazil in July 2020.

While we have commercially launched ONPATTRO and

GIVLAARI, we have limited experience as a commercial company and there is limited information about our ability to successfully overcome many of the risks and uncertainties encountered by companies commercializing products in the biopharmaceutical industry.

We also have several product candidates in late-stage clinical development, including lumasiran, which is under review by the FDA and EMA for marketing approval.

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• build and maintain a strong intellectual property portfolio;

• gain regulatory acceptance for the development and commercialization of our product candidates and market success for ONPATTRO and GIVLAARI, as well as any other products we commercialize;

• gain regulatory acceptance for the development and commercialization of our product candidates and market success for ONPATTRO and GIVLAARI, as well as any other products we commercialize, including in each case, lumasiran;

• attract and retain customers for our products;

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We have experienced significant operating losses since our inception.

As of March 31, 2020, we had an accumulated deficit of $3.91 billion.

As of June 30, 2020, we had an accumulated deficit of $4.09 billion.

Although to date we have launched ONPATTRO in the U.S.

and several other countries globally, launched GIVLAARI in the U.S.

and Germany, and expect to launch our commercially approved products in additional countries during 2020, we may never attain profitability or positive cash flow from operations.

For the quarter ended March 31, 2020, we recognized $71.9 million in net product revenues from sales of ONPATTRO and GIVLAARI.

and several countries in Europe, and expect to launch our commercially approved products in additional countries during 2020, we may never attain profitability or positive cash flow from operations.

For the quarter ended June 30, 2020, we recognized $77.5 million in net product revenues from sales of ONPATTRO and GIVLAARI.

While we believe 2019 was our peak net loss year, we expect to continue to incur annual net operating losses for the foreseeable future and will require substantial resources over the next several years as we expand our efforts to discover, develop and commercialize RNAi therapeutics, and aim to achieve a self-sustainable financial profile.

While we believe the funding provided by Blackstone should enable us to achieve a self-sustainable profile without the need for future equity financing, we will depend on our ability to generate revenues to achieve this goal.

While we believe the funding provided by our strategic financing collaboration with Blackstone should enable us to achieve a self-sustainable profile without the need for future equity financing, we will depend on our ability to generate revenues to achieve this goal.

In addition to revenues derived from sales of our current and future, if any, commercially approved products, we anticipate that a portion of any revenues we generate over the next several years will continue to be from alliances with pharmaceutical and biotechnology companies.

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• progress in our research and development programs, as well as what may be required by regulatory bodies to advance these programs;

• the timing, receipt and amount of milestone and other payments, if any, from present and future collaborators, if any, including milestone payments related to inclisiran, which is being advanced by our partner, MDCO;

• our ability to maintain and establish additional collaborative arrangements and/or new business initiatives;

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Additional funds may not be available to us on acceptable terms or at all.

In April 2020, we entered into a credit agreement, or Credit Agreement, for up to $750.0 million among us, certain of our subsidiaries (together with us, the Loan Parties), funds or accounts managed or advised by GSO Capital Partners LP and certain other affiliates of Blackstone, and the other lenders from time to time party thereto, or Lenders, and Wilmington Trust, National Association, as the administrative agent for the lenders.

In April 2020, we entered into a credit agreement, or Credit Agreement, for up to $750.0 million among us, certain of our subsidiaries (together with us, the Loan Parties), funds or accounts managed or advised by GSO Capital Partners LP and certain other affiliates of Blackstone, and the other lenders from time to time party thereto, collectively, the Lenders, and Wilmington Trust, National Association, as the administrative agent for the lenders.

The Credit Agreement provides for a senior secured delayed draw term loan facility to be funded in three tranches, or Term Loans, each tranche to be requested by certain dates specified in the Credit Agreement, and subject to customary terms and conditions in the case of each tranche.

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The Term Loans mature seven years from the date of the first draw, and bear interest at a variable rate.

All obligations under the Credit Agreement will be secured, subject to certain exceptions, by security interests in certain assets, including the intellectual property owned by us relating to ONPATTRO, GIVLAARI and vutrisiran, the equity interests held by the Loan Parties in their subsidiaries, all of the our ownership of the inclisiran royalty remaining after the royalty purchase and material real property, and certain personal property, including, without limitation, cash held in certain deposit accounts of the Loan Parties and equipment.

All obligations under the Credit Agreement will be secured, subject to certain exceptions, by security interests in certain assets, including the intellectual property owned by us relating to ONPATTRO, GIVLAARI and vutrisiran, the equity interests held by the Loan Parties in their subsidiaries, all of our ownership of the inclisiran royalty remaining after the royalty purchase and material real property, and certain personal property, including, without limitation, cash held in certain deposit accounts of the Loan Parties and equipment.

The Credit Agreement contains negative covenants that, among other things and subject to certain exceptions, could restrict our ability to, incur additional liens, incur additional indebtedness, make investments, including acquisitions, engage in fundamental changes, sell or dispose of assets that constitute collateral, including certain intellectual property, pay dividends or make any distribution or payment on or redeem, retire or purchase any equity interests, amend, modify or waive certain material agreements or organizational documents and make payments of certain subordinated indebtedness.

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In addition, as a condition to providing additional funding to us, future investors may demand, and may be granted, rights superior to those of existing stockholders.

For example, pursuant to our stock purchase agreement with Blackstone, we agreed to register the resale of the shares purchased on a registration statement to be filed with the Securities and Exchange Commission within 60 days of April 10, 2020.

For example, pursuant to our stock purchase agreement with Blackstone, we agreed to register the resale of the shares purchased on a registration statement within 60 days of April 10, 2020, and on June 5, 2020, such registration statement was filed with the Securities and Exchange Commission.

In addition, subject to certain conditions, Blackstone will be entitled to participate in registered underwritten public offerings by us if other selling stockholders are included in the registration.

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The investment of our cash, cash equivalents and marketable debt securities is subject to risks which may cause losses and affect the liquidity of these investments.

As of March 31, 2020, we had $1.34 billion in cash, cash equivalents and marketable debt and equity securities, excluding the $24.7 million of restricted investments related to the security deposit for the lease of our corporate headquarters in Cambridge, Massachusetts and collateral to support letters of credit.

As of June 30, 2020, we had $1.93 billion in cash, cash equivalents and marketable debt and equity securities, excluding the $24.7 million of restricted investments related to the security deposit for the lease of our corporate headquarters in Cambridge, Massachusetts and collateral to support letters of credit.

We historically have invested these amounts in high–grade corporate notes, commercial paper, securities issued or sponsored by the U.S.

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For example, on March 27, 2020, President Trump signed into law the Coronavirus Aid, Relief, and Economic Security Act, or CARES Act, which included certain changes in tax law intended to stimulate the U.S.

economy in light of the COVID-19 outbreak, including temporary beneficial changes to the treatment of net operating losses, interest deductibility limitations and payroll tax matters.

economy in light of the COVID-19 pandemic, including temporary changes to the treatment of

net operating losses, interest deductibility limitations and payroll tax matters.

Future changes in tax laws could have a material adverse effect on our business, cash flow, financial condition or results of operations.

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Risks Related to Our Dependence on Third Parties

We may not be able to execute our business strategy if we are unable to maintain existing or enter into new alliances with other companies that can provide business and scientific capabilities and funds for the development and commercialization

of our product candidates.

If we are unsuccessful in forming or maintaining these alliances on terms favorable to us, our business may not succeed.

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In addition, the occurrence of a fatal thrombotic SAE in our fitusiran study in 2017 could contribute to further concerns about the safety of our therapeutic candidates.

Even when we succeed in securing such alliances, we may not be able to maintain them if, for example, development or approval of a product candidate is delayed, challenges are raised as to the validity or scope of our intellectual property, we are unable to secure adequate reimbursement from payors or sales of an approved drug are lower than we expected.

intellectual property, we are unable to secure adequate reimbursement from payors or sales of an approved drug are lower than we expected.

Furthermore, any delay in entering into collaboration agreements would likely either delay the development and commercialization of certain of our product candidates and reduce their competitiveness even if they reach the market, or prevent the development of certain product candidates.

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If we are not successful in our efforts to enter into future collaboration arrangements with respect to one or more of our product candidates, we may not have sufficient funds to develop these product candidates or other product candidates internally, or to bring our product candidates to market.

If we do not have sufficient

funds to develop and bring our product candidates to market, we will not be able to generate revenues from these product candidates, and this will substantially harm our business.

If we do not have sufficient funds to develop and bring our product candidates to market, we will not be able to generate revenues from these product candidates, and this will substantially harm our business.

If any collaborator materially amends, terminates or fails to perform its obligations under agreements with us, the development and commercialization of our product candidates could be delayed or terminated.

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If any of these occur, the development and commercialization of one or more product candidates could be delayed, curtailed or terminated because we may not have sufficient financial resources or capabilities to continue such development and commercialization on our own.

Although we sold a portion of the expected royalty stream and commercial milestones from the global sales of inclisiran by our collaborator, MDCO, we are entitled to retain the remaining portion of future royalties from the global sales of inclisiran and, if certain specified thresholds are met, to the remaining portion of commercial milestone payments, and any negative developments related to inclisiran could have a material adverse effect on our receipt of those payments.

Although we sold a portion of the expected royalty stream and commercial milestones from the global sales of inclisiran by our collaborator, MDCO (acquired by Novartis AG in January 2020), we are entitled to retain the remaining portion of future royalties from the global sales of inclisiran and, if certain specified thresholds are met, to the remaining portion of

commercial milestone payments, and any negative developments related to inclisiran could have a material adverse effect on our receipt of those payments.

In April 2020, we sold to Blackstone 50% of the royalties payable to us with respect to net sales by MDCO, its affiliates or sublicensees of inclisiran and 75% of the commercial milestone payments payable to us under the MDCO license and collaboration agreement.

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For example, in July 2015, we amended our manufacturing services agreement with Agilent, to provide for Agilent to supply, subject to any conflicting obligations under our third-party agreements, a specified percentage of the active pharmaceutical ingredients required for certain of our product candidates in clinical development, as well as other products the parties may agree upon in the future.

We currently rely on Agilent to supply the active pharmaceutical ingredient to support the commercial supply of ONPATTRO and GIVLAARI, and we have entered into a manufacturing services agreement with Agilent for such supply of ONPATTRO and are finalizing an agreement for the commercial supply of GIVLAARI.

We currently rely on Agilent to supply the active pharmaceutical ingredient to support the commercial supply of ONPATTRO and GIVLAARI, and we have entered into manufacturing services agreements with Agilent for such supply of ONPATTRO and GIVLAARI.

There are risks inherent in pharmaceutical manufacturing that could affect the ability of our CMOs, including Agilent, to meet our delivery time requirements or provide adequate amounts of material to meet our needs.

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In addition to the manufacture of the synthetic siRNAs, we may have additional manufacturing requirements related to the technology required to deliver the siRNA to the relevant cell or tissue type, such as LNPs or conjugates.

In some cases, the delivery technology we utilize is highly specialized or proprietary, and for technical and/or legal reasons, we may have access to only one or a limited number of potential manufacturers for such delivery technology.

In some cases, the delivery technology we utilize is highly specialized or proprietary, and for technical and/or legal reasons, we may have access

to only one or a limited number of potential manufacturers for such delivery technology.

In addition, the scale-up of our delivery technologies could be very difficult and/or take significant time.

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Furthermore, competition for supply from our manufacturers from other companies, a breach by such manufacturers of their contractual obligations or a dispute with such manufacturers would cause delays in our discovery and development efforts, as well as additional expense to us.

On March 27, 2020, President Trump signed into law the CARES Act in response to the COVID-19 pandemic.

Throughout the COVID-19 pandemic, there has been public concern over the availability and accessibility of critical medical products, and the CARES Act enhances FDA’s existing authority with respect to drug shortage measures.

Under the CARES Act, manufacturers must have in place a risk management plan that identifies and evaluates the risks to the supply of approved drugs for certain serious diseases or conditions for each establishment where the drug or active pharmaceutical ingredient is manufactured.

The risk management plan will be subject to FDA review during an inspection.

If we experience shortages in the supply of our marketed products, our results could be materially impacted.

Given the limited number of suppliers for our delivery technology and drug substance, we developed cGMP capabilities and processes for the manufacture of patisiran formulated bulk drug product for late-stage clinical use and commercial supply.

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In developing these manufacturing capabilities by building our own manufacturing facilities, we have incurred substantial expenditures, and expect to incur significant additional expenditures in the future.

addition, the construction and qualification of our drug substance facility is a lengthy process to complete and there are many risks inherent in the construction of a new facility that could result in delays and additional costs, including the need to obtain access to necessary equipment and third-party technology, if any.

In addition, the construction and qualification of our drug substance facility is a lengthy process to complete and there are many risks inherent in the construction of a new facility that could result in delays and additional costs, including the need to obtain access to necessary equipment and third-party technology, if any.

Also, we have had to, and will likely need to continue to, hire and train qualified employees to staff our facilities.

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Nevertheless, we are responsible for ensuring that each of our studies is conducted in accordance with the applicable protocol, legal, regulatory and scientific standards, and our reliance on third parties does not relieve us of our regulatory responsibilities.

We and our CROs are required to comply with applicable GCP requirements, which are regulations and guidelines enforced by the FDA and comparable foreign regulatory authorities for all of our product candidates in clinical development, and to implement timely corrective action to any non-compliance.

We and our CROs are required to comply with applicable

GCP requirements, which are regulations and guidelines enforced by the FDA and comparable foreign regulatory authorities for all of our product candidates in clinical development, and to implement timely corrective action to any non-compliance.

Regulatory authorities enforce these GCP requirements through periodic inspections of trial sponsors, principal investigators and trial sites, including in connection with the review of marketing applications.

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Accordingly, we may be unable to attract and retain suitably qualified individuals in order to support our growing research, development and global commercialization efforts and initiatives, and our failure to do so could have an adverse effect on our ability to implement our future business plan.

Moreover, in response to the spread of COVID-19, we have taken temporary precautionary measures intended to help minimize the risk of the virus to our employees and their families, including implementing a global work from home policy for all employees who are able to perform their duties remotely, and have restricted on-site staff to only those personnel and contractors who must perform essential activities that must be completed on-site, limited the number of staff in any given laboratory, manufacturing facility or other facility and implemented safety practices and procedures for those individuals who are required to work in our facilities, including but not limited to mandatory health screening, the use of face coverings, physical distancing requirements and increased cleaning protocols.

These actions may impair our ability to recruit and/or onboard new employees.

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and EU and other countries globally, and as a result of the January 2018 amendment to our Sanofi Genzyme collaboration, we now have global development and commercialization rights for ONPATTRO.

In addition, we have received regulatory approval for our second RNAi therapeutic, GIVLAARI in the U.S.

and EU , and have also filed for marketing approval in Brazil .

In addition, we have received regulatory approval for our second RNAi therapeutic, GIVLAARI in the U.S., EU , Brazil and have also filed for marketing approval in Canada and Switzerland .

We plan to file for additional regulatory approvals for both ONPATTRO and GIVLAARI in additional countries during 2020 and beyond.

As noted above, we grew our workforce significantly from 2016 through 2019, and anticipate continuing to hire additional employees globally during 2020 as we focus on the commercialization of ONPATTRO and GIVLAARI and achieving our long-term strategic goals.

As noted above, we grew our workforce significantly from 2016 through 2019, and anticipate continuing to hire additional employees globally in the future as we focus on the commercialization of ONPATTRO and GIVLAARI and achieving our long-term strategic goals.

This growth has placed a strain on our administrative and operational infrastructure and, as a result, we will need to continue to develop additional and/or new infrastructure and capabilities to support our growth and obtain additional space to conduct our global operations in the U.S., the EU, Japan, Latin America and other geographies.

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This evolution creates uncertainty and risk of noncompliance with regulations applicable to our business, resulting in potential regulatory actions against us, along with the potential for litigation related to off-label marketing or other prohibited activities.

For example, for our clinical-stage

candidates, patients may use social media channels to comment on their experience in an ongoing blinded clinical study or to report an alleged AE.

For example, for our clinical-stage candidates, patients may use social media channels to comment on their experience in an ongoing blinded clinical study or to report an alleged AE.

When such disclosures occur, there is a risk that study enrollment may be adversely impacted, we fail to monitor and comply with applicable adverse event reporting obligations or that we may not be able to defend our business or the public’s legitimate interests in the face of the political and market pressures generated by social media due to restrictions on what we may say about our investigational products.

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Before obtaining regulatory approval for the commercial distribution of our product candidates, we must conduct, at our own expense, extensive nonclinical tests and clinical trials to demonstrate the safety and/or efficacy in humans of our product candidates.

Nonclinical and clinical testing is expensive, difficult to design and implement, can take many years to complete

and is uncertain as to outcome, and the historical failure rate for product candidates is high.

Nonclinical and clinical testing is expensive, difficult to design and implement, can take many years to complete and is uncertain as to outcome, and the historical failure rate for product candidates is high.

For example, in October 2016, we discontinued development of one of our product candidates, which included a Phase 3 clinical trial.

We currently have multiple other programs in clinical development, including internal and partnered programs in Phase 3 development, as well as several earlier-stage clinical programs.

In December 2019, we reported positive topline results from our ILLUMINATE-A Phase 3 clinical trial for lumasiran, an investigational RNAi therapeutic targeting GO in development for the treatment of PH1, and in April 2020, we submitted an NDA, which was accepted by the FDA, and submitted an MAA, which was granted an accelerated assessment.

The FDA has granted a Priority Review for the NDA and has set an action date of December 3, 2020 under the Prescription Drug User Fee Act, and has indicated that they are not currently planning an advisory committee meeting as part of the NDA review.

Additionally, on March 31, 2020, we submitted an MAA for lumasiran with the EMA, which has been validated by the EMA.

However, we may not be able to further advance this or any other product candidate through clinical trials and regulatory approval.

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Moreover, ONPATTRO, GIVLAARI and our current product candidates, including lumasiran, vutrisiran, fitusiran and inclisiran, each employ novel delivery technologies that, with the exception of inclisiran, have yet to be extensively evaluated in human clinical trials and proven safe and effective.

In addition, we, the FDA or other applicable regulatory authorities, or an institutional review board, or IRB, or similar foreign review board or committee, may delay initiation of or suspend clinical trials of a product candidate at any time for various reasons, including if we or they believe the healthy volunteer subjects or patients participating in such trials are being exposed to unacceptable health risks.

various reasons, including if we or they believe the healthy volunteer subjects or patients participating in such trials are being exposed to unacceptable health risks.

Among other reasons, adverse side effects of a product candidate or related product on healthy volunteer subjects or patients in a clinical trial could result in our decision, or a decision by the FDA or foreign regulatory authorities, to suspend or terminate the trial, or, in the case of regulatory agencies, a refusal to approve a particular product candidate for any or all indications of use.

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In September 2017, we announced that we had temporarily suspended dosing in all ongoing fitusiran studies pending further review of a fatal thrombotic SAE and agreement with regulatory authorities on a risk mitigation strategy.

In December 2017, we reached alignment with study investigators and the FDA on safety measures and a risk mitigation strategy to enable resumption of dosing in clinical studies with fitusiran, including our Phase 2 or OLE, study, and the ATLAS Phase 3 program, including protocol-specified guidelines and additional investigator and patient education concerning reduced doses of replacement factor or bypassing agent to treat any breakthrough bleeds in fitusiran studies.

In December 2017, we reached alignment with study investigators and the FDA on safety measures and a risk mitigation strategy to enable resumption of dosing in clinical studies with fitusiran, including our Phase 2 open-label extension, or OLE, study, and the ATLAS Phase 3 program, including protocol-specified guidelines and additional investigator and patient education concerning reduced doses of replacement factor or bypassing agent to treat any breakthrough bleeds in fitusiran studies.

Clinical trials of a new product candidate require the enrollment of a sufficient number of patients, including patients who are suffering from the disease the product candidate is intended to treat and who meet other eligibility criteria.

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In addition, in November 2018 we announced that due to recruitment challenges, we had discontinued a Phase 2 study of cemdisiran in atypical hemolytic uremic syndrome and are focusing our cemdisiran clinical development efforts in a different indication.

the impact of public health emergencies such as the COVID-19 pandemic, can result in increased costs, longer development times or termination of a clinical trial.

Delays or difficulties in patient enrollment or difficulties retaining trial participants, including as a result of the availability of existing or other investigational treatments or safety concerns, including the impact of public health emergencies such as the COVID-19 pandemic, can result in increased costs, longer development times or termination of a clinical trial.

Although our investigational RNAi therapeutics have been generally well-tolerated in our clinical trials to date, new safety findings may emerge.

For example, as noted above, in September 2017, we announced that we had temporarily suspended dosing in all ongoing fitusiran studies pending further review of a fatal thrombotic SAE that occurred in a patient with hemophilia A without inhibitors who was receiving fitusiran in our Phase 2 open-label extension, or OLE, study.

In addition, in October 2016, we made the decision to discontinue our revusiran program.

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One patient in the givosiran arm discontinued treatment due to an increase in alanine aminotransferase, or ALT, level greater than eight times the upper limit of normal, a protocol-defined stopping rule.

The increase in ALT levels subsequently resolved.

The increase in ALT levels

subsequently resolved.

AEs reported in greater than 10% of givosiran patients and seen more frequently compared to placebo were nausea, ISRs, CKD, and fatigue.

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No patients had clinically significant proteinuria and there were no treatment discontinuations due to renal AEs.

In June 2020, we announced new data from the OLE period of the ENVISION Phase 3 study, which noted that the safety profile of givosiran in the OLE period was consistent with that observed in the double-blind period, and there were no new safety findings.

In our ALN-VSP clinical trial, one patient with advanced pancreatic neuroendocrine cancer with extensive involvement of the liver developed hepatic failure five days following the second dose of ALN-VSP and subsequently died;

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• delays in enrolling patients and volunteers into clinical trials, and variability in the number and types of patients and volunteers available for clinical trials, including as a result of the COVID-19 pandemic;

• disruptions caused by man-made or natural disasters or public health pandemics or epidemics or other business interruptions, including the recent outbreak of COVID-19;

• disruptions caused by man-made or natural disasters or public health pandemics or epidemics or other business interruptions, including the current COVID-19 pandemic;

• high drop-out rates for patients and volunteers in clinical trials;

• negative or inconclusive results from our clinical trials or the clinical trials of others for product candidates similar to ours;

• inadequate supply or quality of product candidate materials or other materials necessary for the conduct of our clinical trials or disruption or delays in the clinical supply due to COVID-19;

• inadequate supply or quality of product candidate materials or other materials necessary for the conduct of our clinical trials or disruption or delays in the clinical supply due to the COVID-19 pandemic;

• greater than anticipated clinical trial costs;

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The lack of policies, practices or guidelines may hinder or slow review by the FDA of any regulatory filings that we may submit.

Moreover, the FDA may respond to these

submissions by defining requirements we may not have anticipated.

Moreover, the FDA may respond to these submissions by defining requirements we may not have anticipated.

Such responses could lead to significant delays in the development of our product candidates.

In addition, because there may be approved treatments for some of the diseases for which we may seek approval, or treatments in development which are approved by the time we apply for approval, in order to receive regulatory approval, we may need to demonstrate through clinical trials that the product candidates we develop to treat these diseases, if any, are not only safe and effective, but safer or more effective than existing products.

In April 2020, we announced that we submitted an NDA and an MAA for lumasiran.

The EMA has granted an accelerated assessment for lumasiran.

In April 2020, we announced that we submitted an NDA for lumasiran, which was accepted by the FDA and granted Priority Review.

The FDA has set an action date of December 3, 2020 under the Prescription Drug User Fee Act, and has indicated that they are not currently planning an advisory committee meeting as part of the NDA review.

Additionally, in March 2020, we submitted an MAA for lumasiran with the EMA, which has been validated by the EMA.

Lumasiran was previously granted an accelerated assessment by the EMA.

Interruption or delays in the operations of the FDA, EMA and comparable foreign regulatory agencies due to the COVID-19 pandemic, may impact the review, inspection and approval timelines for our product candidates, including lumasiran.

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Following any initial regulatory approval of drugs we or our partners may develop, including ONPATTRO, which was approved in the U.S.

and EU in August 2018, and in several other geographies during 2019, and GIVLAARI, which was approved in the U.S.

in November 2019 and in the EU in March 2020, we will also be subject to continuing regulatory oversight, including the review of adverse drug experiences and clinical results that are reported after our drug products are made commercially available.

and EU in August 2018, and in several other geographies thereafter, and GIVLAARI, which was approved in the U.S.

in November 2019, in the EU in March 2020 and in Brazil in July 2020, we will also be subject to continuing regulatory oversight, including the review of adverse drug experiences and clinical results that are reported after our drug products are made commercially available.

This would include results from any post-marketing tests or surveillance to monitor the safety and efficacy of ONPATTRO, GIVLAARI or other drug products required as a condition of approval or agreed to by us.

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If we or our collaborators, CMOs or service providers fail to comply with applicable continuing regulatory requirements in the U.S.

or foreign jurisdictions in which we may seek to market our products, we or they may be subject to, among other things, fines, warning letters, holds on clinical trials, refusal by the FDA or foreign regulatory authorities to approve pending applications or supplements to approved applications, suspension or withdrawal of regulatory approval, product recalls and seizures, refusal to permit the import or export of products, operating restrictions, injunction, civil penalties and criminal prosecution.

applications or supplements to approved applications, suspension or withdrawal of regulatory approval, product recalls and seizures, refusal to permit the import or export of products, operating restrictions, injunction, civil penalties and criminal prosecution.

Even if we receive regulatory approval to market our product candidates, the market may not be receptive to our product candidates upon their commercial introduction, which will prevent us from becoming profitable.

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This could have an adverse impact on the market opportunity for ONPATTRO in the U.S.

In addition, our efforts to raise disease awareness and improve diagnosis of hATTR amyloidosis have also been impacted by the COVID-19 pandemic.

For example, Alnylam Act ® , our third-party genetic screening initiative in the U.S., Canada and Brazil, has experienced a decrease in submitted samples since the pandemic began.

In addition, our efforts to raise disease awareness and improve diagnosis of hATTR amyloidosis have been and may continue to be impacted by the COVID-19 pandemic.

For example, Alnylam Act ® , our third-party genetic screening initiative in the U.S., Canada and Brazil, experienced a decrease in submitted samples in the second quarter as a result of the COVID-19 pandemic.

As is the case with most orphan diseases, if we cannot successfully raise awareness of these diseases and improve diagnosis, it will be more difficult or impossible to achieve profitability.

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Although the FDA and other regulatory agencies that approve drug products do not regulate a physician’s practice of medicine or choice of treatments, the FDA and other regulatory agencies regulate a manufacturer’s communications regarding off-label use and prohibit off-label promotion, as well as the dissemination of false or misleading labeling or promotional materials, including by their agents.

Manufacturers and their agents may not promote drugs for off-label uses or provide off-label information in the promotion of drug products that is not consistent with the approved labeling for those products.

Manufacturers and their agents may not promote drugs for off-label uses or provide off-label information in the promotion of drug products that is not consistent with the approved labeling for those

For example, we may not promote ONPATTRO in the U.S.

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However, a number of our programs are currently in the earlier stages of development and we will not be able to assess the impact of price regulations for such programs for a number of years.

might obtain regulatory approval for a product, including ONPATTRO and GIVLAARI, in a particular country, but then be subject to price regulations that delay our commercial launch of the product and negatively impact the revenues we are able to generate from the sale of the product in that country and potentially in other countries due to reference pricing.

We might obtain regulatory approval for a product, including ONPATTRO and GIVLAARI, in a particular country, but then be subject to price regulations that delay our commercial launch of the product and negatively impact the revenues we are able to generate from the sale of the product in that country and potentially in other countries due to reference pricing.

Our ability to commercialize ONPATTRO, GIVLAARI or any future products, including lumasiran, successfully also will depend in part on the extent to which reimbursement for these products and related treatments will be available from government health administration authorities, private health insurers and other organizations.

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In the U.S., we have entered into more than ten VBAs and are negotiating additional VBAs for ONPATTRO with certain private health insurers.

In addition, we have made significant progress toward establishing VBAs for GIVLAARI.

In addition, we have entered into seven VBAs and are negotiating additional VBAs for GIVLAARI.

The goal of these agreements is to ensure that we are paid based on the ability of our commercially approved products to deliver results in the real world setting comparable to those demonstrated in clinical trials.

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Net prices for drugs may be reduced by mandatory discounts or rebates required by government healthcare programs or private payors and by any future relaxation of laws that presently restrict imports of drugs from countries where they may be sold at lower prices than in the U.S.

For example, on December 18, 2019, President Trump, the U.S.

Department of Health and Human Services, and the FDA issued a notice of proposed rulemaking that, if finalized, would allow for the importation of certain prescription drugs from Canada.

FDA also issued a Draft Guidance document outlining a potential pathway for manufacturers to obtain an additional National Drug Code for an FDA-approved drug that was originally intended to be marketed in a foreign country and that was authorized for sale in that foreign country.

The regulatory and market implications of the notice of proposed rulemaking and Draft Guidance are unknown at this time, but legislation, regulations or policies allowing the reimportation of drugs, if enacted and implemented, could decrease the price we receive for our products and adversely affect our future revenues and prospects for profitability.

On July 24, 2020, President Trump signed four Executive Orders aimed at lowering drug prices.

The Executive Orders direct the Secretary of Health and Human Services to:

eliminate protection under an Anti-Kickback Statute safe harbor for certain retrospective price reductions provided by drug manufacturers to sponsors of Medicare Part D plans or pharmacy benefit managers that are not applied at the point-of-sale;

allow the importation of certain drugs from other countries through individual waivers, permitting the re-importation of insulin products, and prioritizing finalization of the proposed rule to permit the importation of drugs from Canada;

depending on whether pharmaceutical manufacturers agree to other measures, ensure that payment by the Medicare program for certain Medicare Part B drugs is not higher than the payment by other designated countries;

and allow certain low-income individuals receiving insulin and epinephrine purchased by a Federally Qualified Health Center, or FQHC, as part of the 340B drug program to purchase those drugs at the discounted price paid by the FQHC.

The FDA has also issued a Draft Guidance document outlining a potential pathway for manufacturers to obtain an additional National Drug Code for an FDA-approved drug that was originally intended to be marketed in a foreign country and that was authorized for sale in that foreign country.

It is unclear if, when, and to what extent the Executive Orders and the Draft Guidance may be implemented.

The regulatory and market implications of the notice of Executive Orders and Draft Guidance are unknown at this time, but legislation, regulations or policies allowing the reimportation of drugs, if enacted and implemented, could decrease the price we receive for our products and adversely affect our future revenues and prospects for profitability.

Third-party payors often rely upon Medicare coverage policy and payment limitations in setting their own reimbursement rates.

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Specifically, there have been several recent U.S.

Congressional inquiries and proposed federal and state legislation designed to, among other things, bring more transparency to drug pricing, reduce the cost

of prescription drugs under Medicare, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drugs.

Congressional inquiries and proposed federal and state legislation designed to, among other things, bring more transparency to drug pricing, reduce the cost of prescription drugs under Medicare, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drugs.

A number of other legislative and regulatory changes in the healthcare system in the U.S.

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The American Taxpayer Relief Act of 2012, among other things, reduced Medicare payments to several providers and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.

These new laws may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for ONPATTRO,

GIVLAARI or any of our product candidates for which we may obtain regulatory approval, including lumasiran, or the frequency with which ONPATTRO, GIVLAARI or any future product, including lumasiran, is prescribed or used.

These new laws may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for ONPATTRO, GIVLAARI or any of our product candidates for which we may obtain regulatory approval, including lumasiran, or the frequency with which ONPATTRO, GIVLAARI or any future product, including lumasiran, is prescribed or used.

The full effects of the U.S.

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It is unclear whether the ACA will be overturned, repealed, replaced, or further amended.

We cannot predict what affect further changes to the ACA would have on our business.

We cannot predict what affect further changes to the ACA would have

on our business.

The costs of prescription pharmaceuticals in the U.S.

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Department of Health and Human Services is already working to implement.

For example, on October 25, 2018, CMS issued an Advanced Notice of Proposed Rulemaking, or ANPRM, indicating it was considering issuing a proposed rule in 2019 on a model called the International Pricing Index, with a potential start in the spring of 2020.

To date, a proposed rule has not yet been released.

This model would utilize a basket of other countries’ prices as a reference for the Medicare program to use in reimbursing for drugs covered under Part B.

The ANPRM also included an updated version of the Competitive Acquisition Program, as an alternative to current “buy and bill” payment methods for Part B drugs.

Such a proposed rule could limit our product pricing and have material adverse effects on our business.

Although some of these, and other, proposals related to the administration’s Blueprint may require additional authorization to become effective, may ultimately be withdrawn, or may face challenges in the courts, the Congress and the Trump administration have indicated that they will continue to seek new legislative and administrative measures to control drug costs.

Although some proposals related to the administration’s Blueprint may require additional authorization to become effective, may ultimately be withdrawn, or may face challenges in the courts, the Congress and the Trump administration have indicated that they will continue to seek new legislative and administrative measures to control drug costs.

For example, on September 25, 2019, the Senate Finance Committee introduced the Prescription Drug Pricing Reduction Act of 2019, a bill intended to reduce Medicare and Medicaid prescription drug prices.

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and certain foreign export and import controls, sanctions, embargoes, anti-corruption laws, and anti-money laundering laws and regulations.

Compliance with these legal standards could impair our ability to compete in

domestic and international markets.

Compliance with these legal standards could impair our ability to compete in domestic and international markets.

We can face criminal liability and other serious consequences for violations, which can harm our business.

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To obtain reimbursement or pricing approval in some countries, we may be required to conduct a clinical trial that compares the cost-effectiveness of our product candidates to other available therapies.

If reimbursement of our products is unavailable or limited in scope or amount, or if pricing is set at unsatisfactory levels, our ability to generate revenues and become profitable could be impaired.

If reimbursement of our products is

unavailable or limited in scope or amount, or if pricing is set at unsatisfactory levels, our ability to generate revenues and become profitable could be impaired.

In some countries, including Member States of the EU, or Japan, the pricing of prescription drugs is subject to governmental control.

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federal false claims laws, including the FCA, which prohibit, among other things, individuals or entities from knowingly presenting or causing to be presented, claims for payment by government-funded programs such as Medicare or Medicaid that are false or fraudulent, making, using or causing to be made or used a false record or statement material to a false or fraudulent claim to the federal government, or making a false statement to avoid, decrease or conceal an obligation to pay money to the federal government.

Manufacturers can be held liable under the FCA even when they do not submit claims directly to government payors if they are deemed to “cause” the submission

of false or fraudulent claims.

Manufacturers can be held liable under the FCA even when they do not submit claims directly to government payors if they are deemed to “cause” the submission of false or fraudulent claims.

The FCA also permits a private individual acting as a “whistleblower” to bring actions on behalf of the federal government alleging violations of the FCA and to share in any monetary recovery.

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In addition, the GDPR maintains the EU Data Protection Directive’s restrictions on cross-border data transfer.

The GDPR increases the responsibility and liability of pharmaceutical companies in relation to processing personal data, and companies may be required

to put in place additional mechanisms to ensure compliance with the new EU data protection rules.

The GDPR increases the responsibility and liability of pharmaceutical companies in relation to processing personal data, and companies may be required to put in place additional mechanisms to ensure compliance with the new EU data protection rules.

Further, Brexit has created uncertainty with regard to the status of the UK as an “adequate country” for the purposes of data transfers outside the EEA.

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On March 18, 2020, the FDA announced its intention to temporarily postpone routine surveillance inspections of domestic manufacturing facilities and provided guidance regarding the conduct of clinical trials.

As of June 23, 2020, the FDA noted it was conducting mission critical domestic and foreign inspections to ensure compliance of manufacturing facilities with FDA quality standards.

On July 10, 2020, the FDA announced its goal of restarting domestic on-site inspections during the week of July 20, 2020, but such activities will depend on data about the virus’ trajectory in a given state and locality and the rules and guidelines that are put in place by state and local governments.

The FDA has developed a rating system to assist in determining when and where it is safest to conduct prioritized domestic inspections.

Regulatory authorities outside the U.S.

may adopt similar restrictions or other policy measures in response to the COVID-19 pandemic.

If a prolonged government shutdown occurs, or if global health concerns

related to COVID-19 continue to prevent the FDA or other regulatory authorities from conducting certain aspects of their regular review and approval processes within specified or customary time periods, it could significantly impact the ability of the FDA to timely review and process our regulatory submissions, which could have a material adverse effect on our business.

Additionally, as of June 23, 2020, the FDA noted it was continuing to ensure timely reviews of applications for medical products during the COVID-19 pandemic in line with its user fee performance goals;

however, the FDA may not be able to continue its current pace and review timelines could be extended.

If a prolonged government shutdown occurs, or if global health concerns related to COVID-19 continue to prevent the FDA or other regulatory authorities from conducting certain aspects of their regular review and approval processes within specified or customary time periods, it could significantly impact the ability of the FDA to timely review and process our regulatory submissions, which could have a material adverse effect on our business.

Resolving such delays could force us or our collaborators to incur significant costs, could limit our allowed activities or the allowed activities of our collaborators, could diminish any competitive advantages that we or our collaborators may attain or could adversely affect our business, financial condition, results of operations and prospects, the value of our common stock and our ability to bring new products to market as forecasted.

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Following the decision to discontinue clinical development of revusiran, we conducted a comprehensive evaluation of available revusiran data.

We reported the results of this evaluation in August 2017, however, our investigation did not result in a conclusive explanation regarding the cause of the mortality imbalance observed in the ENDEAVOUR Phase 3 study.

We reported the results of this evaluation in August 2017, however, our

investigation did not result in a conclusive explanation regarding the cause of the mortality imbalance observed in the ENDEAVOUR Phase 3 study.

In addition, in September 2017, we announced that we had temporarily suspended dosing in all ongoing fitusiran studies pending further review of a fatal thrombotic SAE and agreement with regulatory authorities on a risk mitigation strategy.

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Department of Labor.

Although we believe that our safety procedures for handling and

disposing of these materials comply with the standards mandated by applicable regulations, the risk of accidental contamination or injury from these materials cannot be eliminated.

Although we believe that our safety procedures for handling and disposing of these materials comply with the standards mandated by applicable regulations, the risk of accidental contamination or injury from these materials cannot be eliminated.

If an accident occurs, we could be held liable for resulting damages, which could be substantial.

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We also rely to a certain extent on trade secrets, know-how and technology, which are not protected by patents, to maintain our competitive position.

If any trade secret, know-how or other technology not

protected by a patent were to be disclosed to or independently developed by a competitor, our business and financial condition could be materially adversely affected.

If any trade secret, know-how or other technology not protected by a patent were to be disclosed to or independently developed by a competitor, our business and financial condition could be materially adversely affected.

Failure to obtain and maintain all available regulatory exclusivities, broad patent scope and to maximize patent term restoration or extension on patents covering our products may lead to loss of exclusivity and early generic entry resulting in a loss of market share and/or revenue.

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There are also many issued patents that claim targeting genes or portions of genes that may be relevant for siRNA drugs we wish to develop.

products, including ONPATTRO and GIVLAARI, or further develop and commercialize future products such as lumasiran and inclisiran, currently under review with the FDA, or continuing to develop candidates in our pipeline being developed by us or our licensees.

In addition, there may be issued and pending patent applications that may be asserted against us in a court proceeding or otherwise based upon the asserting party’s belief that we may need such patents for our siRNA therapeutic candidates or marketed products, including ONPATTRO and GIVLAARI, or further develop and commercialize future products such as lumasiran and inclisiran, currently under review with the FDA, or continuing to develop candidates in our pipeline being developed by us or our licensees.

Thus, it is possible that one or more organizations will hold patent rights to which we may need a license, or hold patent rights which could be asserted against us.

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Some of our competitors may be able to sustain the costs of complex patent litigation more effectively than we can because they have substantially greater resources.

Uncertainties resulting from the initiation and continuation of any litigation could delay our research, development and commercialization efforts and limit our ability to continue our operations.

Uncertainties resulting from the initiation and continuation of any litigation or legal proceeding could delay our research, development and commercialization efforts and limit our ability to continue our operations.

If any parties successfully claim that our creation or use of proprietary technologies infringes upon or otherwise violates their intellectual property rights, we might be forced to pay damages, potentially including treble damages, if we are found to have willfully infringed on such parties’ patent rights.

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In addition, such licenses are likely to be non-exclusive and, therefore, our competitors may have access to the same technology licensed to us.

If we fail to obtain a required license and are unable to design around a patent, we may be unable to effectively market some of our technology and products, which could limit our ability to generate revenues or achieve profitability and possibly prevent us from generating revenue sufficient to

sustain our operations.

Moreover, we expect that a number of our collaborations will provide that royalties payable to us for licenses to our intellectual property may be offset by amounts paid by our collaborators to third parties who have competing or superior intellectual property positions in the relevant fields, which could result in significant reductions in our revenues from products developed through collaborations.

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Our current licenses impose, and any future licenses we enter into are likely to impose, various development, commercialization, funding, milestone, royalty, diligence, sublicensing, insurance, patent prosecution and enforcement, and other obligations on us.

If we breach any of these obligations, or use the intellectual property licensed to us in an unauthorized manner, we may be required to pay damages and the licensor may have the right to terminate the license or render the license non-exclusive, which could result in us being unable to develop, manufacture, market and sell products that are covered by the licensed technology or enable a competitor to gain access to the licensed technology.

non-exclusive, which could result in us being unable to develop, manufacture, market and sell products that are covered by the licensed technology or enable a competitor to gain access to the licensed technology.

Moreover, we could incur significant costs and/or disruption to our business and distraction of our management defending against any breach of such licenses alleged by the licensor.

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In November 2018, we received notice that Ionis had filed a Demand for Arbitration with the Boston office of the American Arbitration Association against us, asserting, among other things, breach of contract.

In December 2018, we filed our answer to Ionis’s Demand for Arbitration, denying any liability to Ionis and the matter is currently in the expert discovery phase.

The arbitration has been set for hearing in the first half of 2020.

While we dispute that additional technology access fees are owed to Ionis, there can be no assurance that we will resolve this matter favorably or that it will not have a material adverse impact on our future results of operations.

In December 2018, we filed our answer to Ionis’s Demand for Arbitration, denying any liability to Ionis.

The hearing portion of the arbitration process was completed in June 2020, and post-hearing briefs were submitted by the parties on July 31, 2020.

Responsive briefs are required to be filed on August 31, 2020.

We now expect a decision from the arbitration panel in late 2020.

While we dispute that any additional technology access fees are owed to Ionis, and also dispute Ionis's claim for interest and attorney's fees in the event that it were to be awarded technology access fees, if it is determined through arbitration that Ionis is entitled to additional technology access fees, we will have to pay Ionis such additional fees, plus potentially interest and attorney's fees on one or more claims.

There can be no assurance that we will resolve this matter favorably or that it will not have a material adverse impact on our future results of operations.

At this time, we are unable to predict the likelihood of a favorable or unfavorable outcome.

Moreover, our licensors may own or control intellectual property that has not been licensed to us and, as a result, we may be subject to claims, regardless of their merit, that we are infringing or otherwise violating the licensor’s rights.

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In August 2018, the FDA approved ONPATTRO lipid complex injection for the treatment of the polyneuropathy of hATTR amyloidosis in adults, and the EC granted marketing authorisation for ONPATTRO for the treatment of hATTR amyloidosis in adults with stage 1 or stage 2 polyneuropathy.

We are aware of other approved products used to treat this disease, including tafamidis, marketed by Pfizer, which is now approved in the U.S., the EU, Japan, Brazil, Argentina, Israel, Russia, South Korea and certain countries in Latin America, and inotersen, developed by Ionis and licensed to Akcea, which is now approved in the U.S., the EU, Canada and Brazil, as well as product candidates in various stages of clinical development, including an additional investigational drug being developed by Ionis.

Finally, we are aware that Eidos Therapeutics, Inc., or Eidos, initiated a Phase 3 clinical trial of AG10, a TTR stabilizer, in ATTR-CM in February 2019.

Eidos also plans to initiate a Phase 3 clinical trial of AG10 in ATTR-PN patients in the first half of 2020.

We are aware of other approved products used to treat this disease, including tafamidis, marketed by Pfizer, which is now approved in the U.S., the EU, Japan,

Brazil, Argentina, Israel, Russia, South Korea and certain countries in Latin America, and inotersen, developed by Ionis and licensed to Akcea, which is now approved in the U.S., the EU, Canada and Brazil, as well as product candidates in various stages of clinical development, including an additional investigational drug being developed by Ionis.

Finally, we are aware that Eidos Therapeutics, Inc., or Eidos, initiated a Phase 3 clinical trial of AG10, a TTR stabilizer, in ATTR-CM in February 2019, and expects enrollment of the Phase 3 clinical trial in ATTR-CM to be completed in the first half of 2021.

Eidos also plans to initiate a Phase 3 clinical trial of AG10 in ATTR-PN patients in the second half of 2020.

While we believe that ONPATTRO has and will continue to have a competitive product profile, it is possible it will not compete favorably with these products and product candidates, or others, and, as a result, may not achieve commercial success.

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Others are following a gene therapy approach, with the goal of treating patients not with synthetic siRNAs but with synthetic, exogenously-introduced genes designed to produce siRNA-like molecules within cells.

Companies working on chemically synthesized siRNAs include, but are not limited to, Takeda Pharmaceutical Company

Ltd., or Takeda, Marina Biotech, Inc., Arrowhead Pharmaceuticals, Inc., or Arrowhead, and its subsidiary, Calando Pharmaceuticals, Inc., or Calando, Quark Pharmaceuticals, Inc., or Quark, Silence, Arbutus, Sylentis, S.A.U., or Sylentis, Dicerna and its collaborators, WAVE Life Sciences Ltd., Arcturus Therapeutics, Inc., and Genevant Sciences, launched by Arbutus and Roivant Sciences.

Companies working on chemically synthesized siRNAs include, but are not limited to, Takeda Pharmaceutical Company Ltd., or Takeda, Marina Biotech, Inc., Arrowhead Pharmaceuticals, Inc., or Arrowhead, and its subsidiary, Calando Pharmaceuticals, Inc., or Calando, Quark Pharmaceuticals, Inc., or Quark, Silence, Arbutus, Sylentis, S.A.U., or Sylentis, Dicerna and its collaborators, WAVE Life Sciences Ltd., Arcturus Therapeutics, Inc., and Genevant Sciences, launched by Arbutus and Roivant Sciences.

In addition, we granted licenses or options for licenses to Ionis, Benitec Biopharma Ltd., Arrowhead, and its subsidiary, Calando, Arbutus, Quark, Sylentis and others under which these companies may independently develop RNAi therapeutics against a limited number of targets.

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For example, the trading price for our common stock and the common stock of other biopharmaceutical companies has been highly volatile during the period of the COVID-19 pandemic.

The COVID-19 outbreak continues to rapidly evolve, and the extent to which the outbreak may impact our business will depend on future developments, which are highly uncertain and cannot be predicted with confidence.

The COVID-19 pandemic continues to rapidly evolve, and the extent to which the pandemic may impact our business will depend on future developments, which are highly uncertain and cannot be predicted with confidence.

These broad market and sector fluctuations have resulted and could in the future result in extreme fluctuations in the price of our common stock, which could cause purchasers of our common stock to incur substantial losses.

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On March 23, 2020, the Court granted our motion and dismissed the Complaint without prejudice.

On April 13, 2020, the plaintiff filed a motion seeking to amend the judgment to permit the plaintiff to file a further amended complaint.

Defendants filed an opposition to that motion on April 17, 2020.

Pursuant to a prior Order of the Court, on June 1, 2020, plaintiff filed a motion seeking leave to file a further amended complaint.

That motion was fully briefed on June 22, 2020, and remains pending with the Court.

We believe that the allegations contained in the now dismissed Complaint are without merit.

However, whether or not the plaintiff’s claims are successful, this type of litigation is often expensive and

diverts management’s attention and resources, which could adversely affect the operation of our business.

However, whether or not the plaintiff’s claims are successful, this type of litigation is often expensive and diverts management’s attention and resources, which could adversely affect the operation of our business.

If we are ultimately required to pay significant defense costs, damages or settlement amounts, in excess of our insurance coverage, such payments could adversely affect our operations.

We may be the target of similar litigation in the future.

For example, on September 12, 2019, the Chester County Employees Retirement Fund, individually and on behalf of all others similarly situated, filed a purported securities class action complaint alleging violation of federal securities laws against us, certain of our current and former directors and officers, and the underwriters of our November 14, 2017 public stock offering, in the Supreme Court of the State of New York, New York County, or the New York State Securities Litigation.

County, or the New York State Securities Litigation.

We believe the allegations in the New York State Securities Litigation, like those in the Complaint described above, are without merit and if our motion to dismiss the case is not successful, we intend to defend the case vigorously.

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A small number of our stockholders beneficially own a substantial amount of our common stock.

As of March 31, 2020, our six largest stockholders beneficially owned in excess of 50% of our outstanding shares of common stock.

As of June 30, 2020, our six largest stockholders beneficially owned in excess of 50% of our outstanding shares of common stock.

If our significant stockholders, or we or our officers and directors, sell substantial amounts of our common stock in the public market, or there is a perception that such sales may occur, the market price of our common stock could be adversely affected.

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These provisions would apply even if the proposed merger or acquisition could be considered beneficial by some stockholders.

10.1†# Patent Cross-License Agreement dated April 3, 2020 between Dicerna Pharmaceuticals, Inc.

and the Registrant.

10.2†# Purchase and Sale Agreement dated April 10, 2020 between BX Bodyguard Royalties L.P.

and the Registrant.

10.3*# Credit Agreement dated April 10, 2020 by and among the Registrant, as Borrower, the Guarantors f rom time to time par ty thereto, the Lenders from time to time party thereto, and Wil mington Trust, National Association , as A dministrative A gent .

10.4 Stock Purchase Agreement by and among the Registrant, as Borrower, and the investors listed in Exhibit A thereto, dated April 10, 2020 (filed as Exhibit 4.2 to the Registrant’s Registration Statement on Form S-3 filed on June 5, 2020 (File No.

333-238989) and incorporated herein by reference).

10.5**# Second Amendment to 2018 Stock Incentive Plan, as amended .

10.6**# Amendment to Amended and Restated 2004 Employee Stock Purchase Plan, as amended .

31.1 Certification of principal executive officer pursuant to Rule 13a-14(a) promulgated under the Securities Exchange Act of 1934, as amended.

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104 Cover Page Interactive Data File (formatted as inline XBRL with applicable taxonomy extension information contained in Exhibits 101.*)

* Schedules, exhibits and similar supporting attachments or agreements to the Credit Agreement are omitted pursuant to Item 601(b)(2) of Regulation S-K.

The Registrant agrees to furnish a supplemental copy of any omitted schedule or similar attachment to the Securities and Exchange Commission upon request.

** Management contracts or compensatory plans or arrangements.

† Portions of this exhibit (indicated by asterisks) have been omitted in accordance with the rules of the Securities and Exchange Commission.

# Filed herewith.

Pursuant to the requirements of the Securities Exchange Act of 1934, the Registrant has duly caused this Report to be signed on its behalf by the undersigned, thereunto duly authorized.

ALNYLAM PHARMACEUTICALS, INC.

May 6, 2020 /s/ John M.

August 6, 2020 /s/ John M.

Maraganore, Ph.D.

1 unchanged sentence

(Principal Executive Officer)

May 6, 2020 /s/ Jeffrey V.

August 6, 2020 /s/ Jeffrey V.

Executive Vice President, Chief Financial Officer

1 unchanged sentence

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-Q

Item 1A. Risk Factors