2020 ANNUAL REPORT

Dedicated to Curing ALS

The ALS Therapy Development Institute (ALS TDI) has a mission to discover and develop effective treatments for ALS. We are the most comprehensive drug discovery lab focused solely on ALS research. Our cutting-edge approach to ALS research incorporates every aspect of drug discovery and development, under one roof, to find potential treatments as quickly as possible.

OUR MISSION

Augie Nieto, ChairmanSteven Perrin, Ph.D., Vice ChairmanStanley Appel, M.D.Kent Bransford, M.D.Alexander CappelloEric CravenJennifer Gore DwyerSteve Fowler, Board Member EmeritusJames Allen HeywoodJohn Heywood, Ph.D., Sc.D.Spiros Jamas, Sc.D.

Bashar Al-Nakhala, COOJosh BermanChelsea BlandaAlessandro CaloKyle Denton, Ph.D.Emily DhondtLaura FelixMatthew FerolaJonathan GangAlan Gill, Ph.D.Anna GillCynthia GillAlison GuzzettiCarol HamiltonTerri HandlerTheo Hatzipetros, Ph.D.Josh KiddMeghan LawlorDavid LeBlanc

Beth LevineMatvey Lukashev, Ph.D.Meghan ManiaCarlos MayaGlynis MurrayAndy MorenoKaly MuellerRoxanne MurdenAlan PremasiriClare ReichCarolyn RodgersRicardo SanchezMike ShannonShawn SullivanVal TassinariKen ThompsonFernando Vieira, M.D., CEO/CSOBen WakefieldYiding Yan

Board of DirectorsAs of September 2021

StaffAs of September 2021

Leslie MichelsonAndrew Niblock Lynne NietoTheodore Reich, Treasurer and Audit Committee Chair Rob Rodin, Executive Compensation Committee ChairPaul A. SallaberryRobert Sepucha Michael M. SmithJulie Swan

LETTER FROM THE CEO

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Dear Friend,

The past year has been unprecedented in so many ways. Certainly, we have all confronted uncertainties and hardships. But 2020 has been unique in positive ways as well. I have been deeply inspired to see the ALS community continue to support ALS TDI’s work during a time when we needed it the most. I have also been proud to see the team at ALS TDI persevere through the year – scientists adapting to new safety protocols, working odd hours, adjusting to working from home, and pivoting on projects to advance our mission as quickly as possible.

And so, thanks to your unwavering support, your team of scientists at ALS TDI accomplished most of our goals in 2020. I’d like to share some highlights with you here.

• We began a drug screening initiative – beginning to test our library of 36,000 small molecules using neural cells derived from human induced pluripotent stem cells.

• We have begun lead discovery assessments of early hits from the drug screening campaign using in vivo models with promising molecules demonstrating efficacy in mice with ALS.

• We have been analyzing blood samples from the Precision Medicine Program’s (PMP) In-Home Blood Collection Initiative to discover and validate blood-based biomarkers of ALS disease progression.

• We enrolled more than 85 new participants into the PMP to allow for the comprehensive study of ALS symptom progression, genetics, risk factors, biomarkers, and outcomes from interventions.

• We published a paper in Frontiers in Pharmacology where we shared our discovery of a previously unexplored drug target for C9ORF72-mediated ALS.

As we look to 2021, I am truly excited for all that we are poised to accomplish. We are thrilled to be moving to a new state-of-the-art lab space in Watertown, MA this coming March. This new 16,000 square foot space has been customized to accommodate our comprehensive approach to ALS research. In this lab, under one roof, our preclinical, clinical, and translational research teams will continue to work relentlessly to end ALS.

While am extremely proud of what we have accomplished, we must continue to work until there are treatments for every single person living with ALS.

I am excited to seize on the opportunities that we have created through our recent discoveries, I am inspired by the team of scientists that I get to be a part of, and I am encouraged by the support of the ALS community and your faith in us. I look forward to sharing our continued progress with you.

With sincere thanks for your continued support,

Fernando Vieira, M.D.Chief Executive Officer and Chief Scientific Officer, ALS Therapy Development Institute

2020 was a year unlike any other in the history of the ALS Therapy Development Institute, or the world. Faced with the challenges of the COVID-19 pandemic, we had to adapt many aspects of our research – and the fundraising that supports it – to accommodate the need for social distancing. With the dedication of the ALS TDI Team and the support of the ALS community, however, we were able to maintain the pace of essential research and achieve our goals.

Fundraisers and Events Go Virtual: In order to maintain social distancing, many of our signature events had to go virtual in 2020. The Tri-State Trek became the My-State Trek. The #wearetrekfamily joined together online through Strava, Zwift, and Zoom to ride, run, and walk all over the country and the world to raise money for essential research at ALS TDI. The ALS TDI Leadership Summit and White Coat Affair gala moved online as well, with many of our supporters joining us on Zoom to learn about ALS TDI’s latest research while supporting and celebrating our mission to end ALS.

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MOVING RESEARCH FORWARD AMID THE COVID-19 PANDEMIC

Maintaining the Pace of ResearchALS TDI’s commitment to efficiency made us uniquely poised to continue our most vital research throughout all stages of the pandemic. At the start of the pandemic, efficiencies we already had in place, such as automation systems, robots, and a telemedicine-based clinical research program, allowed us to remotely continue critical projects like cell-based drug screens and the Precision Medicine Program (PMP). In addition, essential members of the science team continued to go into the lab in shifts. As restrictions eased, we developed safety protocols to ensure that all members of our science team could safely return to the lab to resume full operations.

The Community Steps UpIn addition to our own events, ALS TDI community members provided invaluable to support to the organization through their own fundraisers. Through the #Handlebars4Hope campaign, led by our valued supporters Matt Bellina and the late Pat Quinn, people all over the country shaved funny mustaches and shared the images on social media to solicit over $40,000 in donations for our research. Working around COVID restrictions, Racing for ALS was able to put on a socially distanced edition of the Dave’s Race driving event, raising more than $50,000. Our community was also invaluable in helping us to weather the earliest days of the pandemic, donating over $346,000 in response to our emergency COVID-19 appeal in the spring.

could be protective against C9orf72 ALS, as well as C9orf72 frontotemporal dementia (FTD).

In 2021, ALS TDI scientists will work to advance this discovery and bring us closer to finding drugs that could address this new target. The next steps include determining a specific PRMT to target, exploring the biology of type I PRMTs in additional model systems like human iPSC cells, zebrafish, and mice, finding safe drug-like compounds that address the target, and further studying arginine methylation and PRMT activity in people with ALS through samples taken in our Precision Medicine program. The authors have also already published a second paper outlining several theories as to the mechanisms by which the target might be protective for motor neurons and encouraging others in the field to study these findings and work toward potential therapies.

We explore the possibilities. In September of 2020, despite the many challenges of the COVID-19 pandemic, ALS TDI scientists were able to publish a paper outlining evidence implicating a previously unexplored therapeutic target for C9orf72-mediated ALS. The paper titled, Type I PRMT inhibition protects against C9ORF72 arginine-rich dipeptide repeat toxicity, was authored by ALS TDI scientists, Alan Premasari, Anna Gill, and Fernando Vieira, M.D.

The study demonstrated that by inhibiting certain PRMTs (a class of enzymes that post-translationally modify proteins), scientists were able to protect against C9orf72 arginine-rich dipeptide repeat toxicity. Specifically, they found that they could protect cells from C9orf72 dipeptide repeat toxicity by inhibiting the PRMTs that cause asymmetric dimethylation, a specific molecular modification, to the amino acid, arginine. The results suggest that inhibition of asymmetric dimethylation

2020 was a uniquely challenging year, but ALS TDI’s researchers continued to adapt and relentlessly move forward our mission to find effective cures and treatments for ALS.

RESEARCH ACCOMPLISHMENTS

We are efficient. We began to rapidly screen drugs from a 36,000-compound library that we acquired in 2019. The drugs are screened using neural cells derived from human induced pluripotent stem cells (iPSCs). Some of the early hits have been advanced to lead discovery using in vivo models.

We learn from you. In 2020 we enrolled 85 people (goal of 100 more people) in our Precision Medicine Program (PMP), enabling participants to access helpful tools while allowing ALS TDI researchers to study data on symptom progression, genetics and other risk factors, biomarkers, and interventions.

We dig data. We began analyzing samples from the PMP’s In-Home Blood Collection Initiative to discover and validate blood-based biomarkers of ALS disease progression. We explored neurofilament light chain, among other biomarkers, because there is evidence that this could predict rate of ALS progression.

We are innovative. We continued to study an even more versatile and comprehensive selection of ALS models.

We imported a zebrafish model of C9orf72-mediated ALS in collaboration with researchers at the University of Sheffield in the United Kingdom to characterize and optimize for drug screening in house.

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LEADERS IN THE ALS COMMUNITY2020 has been a year unlike any other. Facing a global pandemic, economic uncertainty, and the realities of lockdowns, quarantines, and social distancing, the ALS community still found many creative ways to stay strong and united, even from afar. The support of this community has been incredibly important to keeping our research to end Amyotrophic Lateral Sclerosis (ALS) at ALS TDI going, despite the many challenges we’ve all faced this year.

As part of this year’s ALS TDI Summit, a free conference about ALS TDI’s latest research, we recognized a few community members, nominated by their peers, whose efforts truly stood out this year.

PHIL GREEN Stephen Heywood Patients Today Award Phil Green is a former University of Washington football player and father of four who was diagnosed with ALS in 2018. Since his diagnosis, he has been relentless in spreading awareness about the disease and supporting research to end it – as an advocate and a participant. Earlier this year he lent his voice to a campaign to support ALS TDI’s Precisions Medicine Program – in which he is himself enrolled – helping us to continue to learn about ALS from people with ALS. He also participated in Brainstorm’s NurOwn trial, served as an ALS Association roundtable member, and has participated in many biotech and pharmaceutical industry advisory panels. Phil has also joined the International Symposium on ALS/MND through the Patient Fellows Program.

SANDY MORRISStephen Heywood Patients Today Award Sandy Morris, a mother of three who was also diagnosed with ALS in 2018, has brought a similar determination to advance and support ALS research to her fight against the disease. She has been active in creating resources to help people with ALS get help they need with I AM ALS, working with Biotech and Pharma companies to make sure they listen to patients when they design clinical trial protocols and has made many trips to Washington D.C. to educate members of Congress about ALS.

BRYAN WAYNE GALENTINEThe Interconnected Award Specially named for this unprecedented year, the ALS TDI Interconnected Award is presented to a member of the ALS community who has demonstrated an unwavering commitment to keeping the community educated and engaged throughout the COVID-19 pandemic.

Bryan Wayne Galentine was, sadly, presented with the award posthumously. He passed from complications due to ALS on October 22nd at the age of 53. Bryan was a singer-songwriter living in Tennessee, who was diagnosed with ALS in 2017. Throughout the years following his diagnosis, Bryan spearheaded a number of projects to bring the ALS community together.

His “What’s your Omelet” mantra encouraged people to live in the moment. This mantra was based on his determination, after receiving his ALS diagnosis, to accomplish something simple he had always wanted to do – learning how to make an omelet.

“It could be big bucket list stuff like skydiving or climbing Mt. Everest on down to learning how to play guitar, speak French or paint,” he wrote in a Facebook post describing his philosophy. “In my case, it was learning how to make an omelet. Get it? The point is: life is short, quit putting things off, don’t wait just do it! So – What’s YOUR Omelet??”

Bryan raised money and awareness for ALS by selling T-shirts and other merchandise with this slogan, as well as with the sales of his album While You Wait, which he wrote and produced with many of his friends in the Nashville songwriting community. He was an advisory board member of I AM ALS, and was also instrumental in the campaign to establish an annual Major League Baseball event celebrating Lou Gehrig, Lou Gehrig Day. In early November, a few weeks after his passing, it was announced that the initiative had the support of all 30 MLB teams.

2015 2016 2017 2018 2019 2020 Total Spent

Program Services $11,257,021 $9,705,301 $10,771,564 $10,587,060 $10,039,201 $8,466,048 $60,826,195

Support Services $1,425,127 $1,569,649 $1,766,028 $1,815,788 $1,442,668 $1,103,743 $9,123,003

$12,000,000

$10,000,000

$8,000,000

$6,000,000

$4,000,000

$2,000,000

Program Services Support Services$0

2015 2016 2017 2018 2019 2020

Liabilities & Net Assets

Current Liabilities $325,112

Long Term Liabilities $2,467,712

Net Assets $27,204,165

Total Liabilities & Net Assets $29,996,989

Grants $174,877

Special Events, Net $6,886,760

Contributions $1,710,496

Released from Restrictions $320,750

Fee for Service $265,315

Donated Goods & Services $42,965

Interest & Other $107,742

Operating Income

Total Public Support $9,508,905

Total Expenses $9,569,791

Operating Expenses

Program

R&D

Science $6,255,844

Informatics $721,744

Patient Services $58,827

Communications $1,373,975

Business Development $55,658

Total Program $8,466,048

Support

General Fund $825,077

Fundraising $278,666

Total Support $1,103,743

Current Assets

Cash And Cash Equivalents $7,459,500

Pledges & Accounts Receivable $206,940

Other Current Assets* $637,139

Other Assets

Pledges Receivable -

Property & Equipment, Net $282,980

Patents $707,689

Investment in Subsidiary $20,414,009

Other Long Term Assets $288,732

Assets

Total Assets $29,996,989

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2015-2020 A FINANCIAL COMPARISON

FINANCIAL REVIEW

**Ledford, H. “Keeping the Lights On.” Nature, 20 November 2014

As a nonprofit, we rely on donations to accelerate our research. 87 cents of every dollar goes directly to finding treatments and cures at ALS TDI, compared to the average 75 cents** at other research labs, and we have been rated a four-star nonprofit by Charity Navigator for five years in a row.

ALS TDI financial information for fiscal year ending December 31, 2020.

This financial information is derived from audited financial statements. Copies of audited financial statements are available upon request. For a complete copy of our IRS Form 990 or Independent Auditors Report, please call us at 617.441.7200.

* This financial information is derived from audited financial statements, available upon request.

480 Arsenal Street, Suite 201, Watertown, MA 02472 617.441.7200 | www.als.net