On April 28, 2022 Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, reported its consolidated financial results for the first quarter ended March 31, 2022 and reviewed recent business highlights (Press release, Alnylam, APR 28, 2022, View Source [SID1234613115]).

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"The first quarter of 2022 saw a steady increase in patients on therapy across all products in our commercial portfolio, despite combined product revenues that were down compared to Q4 2021, as anticipated, given several non-recurring revenue benefits in the fourth quarter of 2021, as well as some pandemic-related impact experienced early in the quarter. We continue to make progress with our pipeline programs, including our TTR franchise, for which we reported positive 18-month results from the HELIOS-A study of vutrisiran, and we remain on track for topline results from the APOLLO-B study of patisiran in the middle of this year," said Yvonne Greenstreet, MBChB, MBA, Chief Executive Officer of Alnylam. "With our earlier stage programs, we’re excited to have initiated our first clinical study of an Alnylam investigational RNAi therapeutic targeting a CNS disorder with the start of our Phase 1 study for ALN-APP in patients with early-onset Alzheimer’s disease, and are announcing today that the Phase 1 study of ALN-XDH in patients with gout also has been initiated. These programs underscore our commitment to advancing innovative new medicines into the clinic, and we anticipate data from both programs later this year. We look forward to continuing our steady execution across our commercial products and advancement of our clinical development pipeline, with many key upcoming milestones to mark our progress toward achieving our Alnylam P5x25 strategy."

First Quarter 2022 and Recent Significant Corporate Highlights

Commercial Performance

ONPATTRO (patisiran)

Achieved global net product revenues for the first quarter of 2022 of $137 million, representing a 1% decrease compared to Q4 2021.
Attained over 2,200 hATTR amyloidosis patients with polyneuropathy worldwide on commercial ONPATTRO treatment as of March 31, 2022, up from over 2,050 commercial patients at year end 2021, representing 7% quarterly growth.
GIVLAARI (givosiran)

Achieved global net product revenues for the first quarter of 2022 of $35 million, representing a 13% decrease compared to Q4 2021.
Attained over 400 patients worldwide on commercial GIVLAARI treatment as of March 31, 2022, up from over 350 commercial patients at year end 2021, representing 14% quarterly growth.
OXLUMO (lumasiran)

Achieved global net product revenues for the first quarter of 2022 of $15 million, representing a 24% decrease compared to Q4 2021.
Attained over 160 patients worldwide on commercial OXLUMO treatment as of March 31, 2022, up from over 140 commercial patients at year end 2021, representing 14% quarterly growth.
Leqvio (inclisiran)

Launch in the U.S. and in other markets is ongoing, with focus on patient on-boarding, removing access hurdles and driving urgency to treat. Leqvio is now approved in more than 55 countries, with most awaiting reimbursement.
R&D Highlights

Vutrisiran, a subcutaneously administered investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis and Stargardt disease

Reported positive results for 18-month endpoints and safety from the HELIOS-A Phase 3 study in hATTR amyloidosis patients with polyneuropathy.
Vutrisiran met all 18-month secondary endpoints, including statistically significant improvements in neuropathy impairment, quality of life (QoL), gait speed, nutritional status and overall disability, relative to external placebo.
Vutrisiran continued to demonstrate halting or reversal of polyneuropathy, with improvements in neuropathy impairment and QoL, relative to baseline.
Additionally, vutrisiran continued to demonstrate an encouraging safety and tolerability profile.
At month 18, vutrisiran also showed improvements in exploratory cardiac endpoints, including NT-proBNP, a measure of cardiac stress; certain echocardiographic parameters, relative to placebo; and technetium uptake in the heart, providing potential evidence for reduced cardiac amyloid burden.
Announced that the U.S. Food and Drug Administration (FDA) has extended the review timeline of the New Drug Application (NDA) for vutrisiran to allow for review of newly added information related to the new secondary packaging and labeling facility.
The updated Prescription Drug User Fee Act (PDUFA) goal date to allow for this review is July 14, 2022. No additional clinical data have been requested by the FDA.
Vutrisiran is also under review by the European Medicines Agency (EMA), the Brazilian Health Regulatory Agency (ANVISA) and the Japanese Pharmaceuticals and Medical Devices Agency (PMDA).
Lumasiran (the non-proprietary name for OXLUMO), for the treatment of primary hyperoxaluria type 1 (PH1), and in development for the treatment of recurrent kidney stone disease

Announced U.S. FDA acceptance of the Company’s supplemental NDA for OXLUMO for the treatment of advanced PH1.
The FDA has set a PDUFA goal date of October 6, 2022.
Additionally, a Type II variation for lumasiran to amend the label to further inform on the use of lumasiran in patients with advanced PH1 was submitted in December 2021 and is undergoing review by the Committee for Medicinal Products for Human Use (CHMP) with a decision expected by year-end.
Early- and mid-stage investigational RNAi therapeutic pipeline programs and RNAi platform

Initiated a Phase 1 study of ALN-APP in patients with early-onset Alzheimer’s disease (EOAD).
The Company announces today that it has initiated a Phase 1 study of ALN-XDH in patients with gout.
The Company announces today that, due in part to impacts related to COVID-19 as well as the ongoing situation in Ukraine, it now expects to complete enrollment in the KARDIA-1 Phase 2 monotherapy study of zilebesiran in patients with mild-to-moderate hypertension in early 2023, with topline results now expected in mid-2023.
Vir Biotechnology reported encouraging results from its Phase 2 trial evaluating ALN-HBV02 (VIR-2218), an investigational RNAi therapeutic in development for the treatment of chronic hepatitis B virus (HBV) infection, in combination with its investigational monoclonal antibody VIR-3434.
Additional Business Updates

Appointed Akshay Vaishnaw, M.D., Ph.D., formerly President, Research and Development, as President effective January 1, 2022.
Appointed Indrani Franchini as Chief Legal Officer effective January 31, 2022.
Entered into a collaboration with Novartis to explore a targeted therapy designed to promote the regrowth of functional liver cells and to provide an alternative to transplantation for patients with liver failure.
Launched a partnership with Our Future Health, the UK’s largest ever health research program that aims to genotype samples from up to 5 million participants.
Published 2021 Corporate Responsibility Report.
Filed separate patent infringement suits against Pfizer, Inc. and Moderna, Inc., seeking damages for infringement of U.S. Patent No. 11,246,933 in the parties’ manufacture and sale of their messenger RNA (mRNA) COVID-19 vaccines. The patent relates to Alnylam’s biodegradable cationic lipids that are foundational to the success of the mRNA COVID-19 vaccines.
Upcoming Events

In early and mid-2022, Alnylam intends to:

Launch vutrisiran in the U.S., assuming successful review and approval from the FDA, for the treatment of hATTR amyloidosis patients with polyneuropathy.
Report topline results from the APOLLO-B Phase 3 study of patisiran in ATTR amyloidosis patients with cardiomyopathy.
Report results from the Phase 2 monotherapy study of cemdisiran in patients with IgA nephropathy.
Novartis plans to report results from its ORION-3 Phase 2 study of inclisiran in patients with heterozygous familial hypercholesterolemia or pre-existing atherosclerotic cardiovascular disease on background statin +/- ezetimibe therapy.
Report topline results from Part B of the Phase 1 study of ALN-HSD in patients with NASH.
Financial Results for the Quarter Ended March 31, 2022

Net Product Revenues

Net product revenues increased 38% compared to the first quarter of 2021, primarily due to increased patients on ONPATTRO, GIVLAARI, and OXLUMO therapies, offset by an unfavorable impact from foreign exchange rates on our international revenue.
Net Revenues from Collaborations

Net revenues from collaborations decreased 38% compared to the first quarter of 2021, primarily due to a decrease in revenue from our collaboration with Regeneron.
First Quarter 2022 Expenses

Research & Development (R&D) Expenses

GAAP R&D expenses decreased compared to the first quarter of 2021, primarily due to decreased stock-based compensation expense primarily due to the accounting for certain performance-based awards.
Selling, General & Administrative (SG&A) Expenses

GAAP and Non-GAAP SG&A expenses increased compared to the first quarter of 2021, primarily due to increased legal expenses, charitable contributions, and other expenses to support our strategic growth. On a GAAP basis, these increases were offset by decreased stock-based compensation expense primarily due to the accounting for certain performance-based awards.
Other Financial Highlights

GAAP other expense increased compared to the first quarter of 2021, primarily due to approximately $80 million of realized and unrealized losses on our marketable equity securities holdings and an increase in interest expenses of approximately $10 million due to additional draws on our term loan facility.
Cash, cash equivalents and marketable securities were $2.24 billion as of March 31, 2022 compared to $2.44 billion as of December 31, 2021 with the decrease primarily due to our operating loss in the first quarter of 2022.
A reconciliation of our GAAP to non-GAAP results for the current quarter is included in the tables of this press release.

2022 Updated Financial Guidance
Full year 2022 financial guidance has been updated as follows:

Use of Non-GAAP Financial Measures

This press release contains non-GAAP financial measures, including expenses adjusted to exclude certain non-cash expenses and non-recurring gains outside the ordinary course of the Company’s business. These measures are not in accordance with, or an alternative to, GAAP, and may be different from non-GAAP financial measures used by other companies.

The items included in GAAP presentations but excluded for purposes of determining non-GAAP financial measures for the periods presented in this press release are stock-based compensation expenses and realized and unrealized (gains) losses on marketable equity securities. The Company has excluded the impact of stock-based compensation expense, which may fluctuate from period to period based on factors including the variability associated with performance-based grants for stock options and restricted stock units and changes in the Company’s stock price, which impacts the fair value of these awards. The Company has excluded the impact of the realized and unrealized (gains) losses on marketable equity securities because the Company does not believe these adjustments accurately reflect the performance of the Company’s ongoing operations for the period in which such gains or losses are reported, as their sole purpose is to adjust amounts on the balance sheet.

The Company believes the presentation of non-GAAP financial measures provides useful information to management and investors regarding the Company’s financial condition and results of operations. When GAAP financial measures are viewed in conjunction with non-GAAP financial measures, investors are provided with a more meaningful understanding of the Company’s ongoing operating performance and are better able to compare the Company’s performance between periods. In addition, these non-GAAP financial measures are among those indicators the Company uses as a basis for evaluating performance, allocating resources and planning and forecasting future periods. Non-GAAP financial measures are not intended to be considered in isolation or as a substitute for GAAP financial measures. A reconciliation between GAAP and non-GAAP measures is provided later in this press release.

Conference Call Information

Management will provide an update on the Company and discuss first quarter 2022 results as well as expectations for the future via conference call on Thursday, April 28, 2022 at 8:30 am ET. To access the call, please dial 877-312-7507 (domestic) or +1-631-813-4828 (international) five minutes prior to the start time and refer to conference ID 2758447. A replay of the call will be available beginning at 11:30 am ET on the day of the call. To access the replay, please dial 855-859-2056 (domestic) or +1-404-537-3406 (international) and refer to conference ID 2758447.

A live audio webcast of the call will be available on the Investors section of the Company’s website at www.alnylam.com/events. An archived webcast will be available on the Alnylam website approximately two hours after the event.

About ONPATTRO (patisiran)

ONPATTRO is an RNAi therapeutic that was approved in the United States and Canada for the treatment of the polyneuropathy of hATTR amyloidosis in adults. ONPATTRO is also approved in the European Union, Switzerland and Brazil for the treatment of hATTR amyloidosis in adults with Stage 1 or Stage 2 polyneuropathy, and in Japan for the treatment of hATTR amyloidosis with polyneuropathy. ONPATTRO is an intravenously administered RNAi therapeutic targeting transthyretin (TTR) and should be administered via a healthcare professional. It is designed to target and silence TTR messenger RNA, thereby blocking the production of TTR protein before it is made. ONPATTRO blocks the production of TTR in the liver, reducing its accumulation in the body’s tissues in order to halt or slow down the progression of the polyneuropathy associated with the disease. For more information about ONPATTRO, including please see the full U.S. Prescribing Information, visit ONPATTRO.com.

About GIVLAARI (givosiran)

GIVLAARI is an RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) approved in the United States and Brazil for the treatment of adults with acute hepatic porphyria (AHP). GIVLAARI is also approved in the European Union for the treatment of AHP in adults and adolescents aged 12 years and older. In the pivotal study, givosiran was shown to significantly reduce the rate of porphyria attacks that required hospitalizations, urgent healthcare visits or intravenous hemin administration at home compared to placebo. GIVLAARI is Alnylam’s first commercially available therapeutic based on its Enhanced Stabilization Chemistry ESC-GalNAc conjugate technology to increase potency and durability. GIVLAARI is administered via subcutaneous injection once monthly at a dose based on actual body weight and should be administered by a healthcare professional. GIVLAARI works by specifically reducing elevated levels of ALAS1 messenger RNA (mRNA), leading to reduction of toxins associated with attacks and other disease manifestations of AHP. For more information about GIVLAARI, including the full U.S. Prescribing Information, visit GIVLAARI.com.

About OXLUMO (lumasiran)

OXLUMO is an RNAi therapeutic targeting hydroxyacid oxidase 1 (HAO1) for the treatment of primary hyperoxaluria type 1 (PH1) to lower urinary oxalate levels in pediatric and adult patients. HAO1 encodes glycolate oxidase (GO), an enzyme upstream of the disease-causing defect in PH1. OXLUMO works by degrading HAO1 messenger RNA and reducing the synthesis of GO, which inhibits hepatic production of oxalate – the toxic metabolite responsible for the clinical manifestations of PH1. In the pivotal ILLUMINATE-A study, OXLUMO was shown to significantly reduce levels of urinary oxalate relative to placebo, with the majority of patients reaching normal or near-normal levels. Injection site reactions (ISRs) were the most common drug-related adverse reaction. In the ILLUMINATE-B pediatric Phase 3 study, OXLUMO demonstrated an efficacy and safety profile consistent to that observed in ILLUMINATE-A. OXLUMO utilizes Alnylam’s Enhanced Stabilization Chemistry (ESC)-GalNAc conjugate technology designed to increase potency and durability. OXLUMO is administered via subcutaneous injection once monthly for three months, then once quarterly thereafter at a dose based on actual body weight. For patients who weigh less than 10 kg, ongoing dosing remains monthly. OXLUMO should be administered by a healthcare professional. For more information about OXLUMO, including the full U.S. Prescribing Information. visit OXLUMO.com.

About LNP Technology

Alnylam has licenses to Arbutus Biopharma LNP intellectual property for use in RNAi therapeutic products using LNP technology.

About RNAi

RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines known as RNAi therapeutics is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam’s RNAi therapeutic platform, function upstream of today’s medicines by potently silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing or disease pathway proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.