On November 5, 2020 Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, reported its consolidated financial results for the third quarter 2020 and reviewed recent business highlights (Press release, Alnylam, NOV 5, 2020, View Source [SID1234570014]).
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"We are extremely pleased with the performance of ONPATTRO and GIVLAARI in the third quarter, reflecting strong commercial execution and improving market conditions following the more challenging COVID-19 pandemic phase experienced in the second quarter. We’re also excited about the recent positive CHMP opinions for OXLUMO and LEQVIO, moving these potentially transformative investigational RNAi therapeutics closer to approval. We believe that this positions Alnylam to potentially exit 2020 with four revenue-generating products bolstering our sustained growth," said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. "In addition, our robust late-stage pipeline of investigational medicines continued to advance in the quarter. Notably, we achieved positive results from the ILLUMINATE-B study – demonstrating efficacy and safety for our investigational RNAi therapeutic lumasiran in children under the age of six, including infants. We also achieved continued enrollment in our APOLLO-B and HELIOS-B Phase 3 studies of patisiran and vutrisiran, respectively, in development for the treatment of ATTR amyloidosis with cardiomyopathy. With our recent progress, we now expect to exceed our Alnylam 2020 vision and goals of building a multi-product, global biopharma company with a deep clinical pipeline and a robust, organic product engine to drive future sustainable innovation and value creation. Finally, we look forward to highlighting further progress and future plans at our upcoming virtual R&D Day event in December."
Third Quarter 2020 and Recent Significant Corporate Highlights
Commercial Performance
ONPATTRO
Achieved global net product revenue for the third quarter of 2020 of $82.5 million, representing 24% quarterly growth globally and 21% quarterly growth in the U.S. alone.
Attained over 1,150 patients worldwide on commercial ONPATTRO treatment as of September 30, 2020.
Continued progress with market access efforts across the CEMEA region (Canada, Europe, Middle East, and Africa), with a recent launch in Portugal, conclusion of price negotiations in France, and completion of initial access agreement in Canada.
Continued global expansion with achievement of regulatory approval in Israel.
Received the prestigious 2020 Prix Galien USA Award for Best Biotechnology Product.
GIVLAARI
Achieved global net product revenue for the third quarter of 2020 of $16.7 million.
Attained over 150 patients worldwide on commercial GIVLAARI treatment as of September 30, 2020.
Continued strong market access progress in the U.S., with 10 VBAs finalized to date with commercial payers and confirmed access for over 90% of covered U.S. lives.
Continued progress with market access efforts across the CEMEA region, with ongoing launch in Germany, cohort Temporary Authorization for Use (ATU) supply in France, and named patient sales in other countries.
Received an Improvement of Medical Benefit (ASMR) score of II in France, concluding that GIVLAARI offers significant additional therapeutic value. In 2019, only two new commercial medicines received a similar ASMR score.
In addition, obtained a "Considerable Benefit" rating in Germany and secured a strong health technology assessment (HTA) rating in Italy.
Continued global expansion with approval in Canada and submission of a new drug application in Japan.
Received the NORD 2020 Industry Innovation Award.
R&D Highlights
Advanced patisiran (the non-proprietary name for ONPATTRO), in development for the treatment of the cardiomyopathy of both hereditary and wild-type ATTR amyloidosis.
Continued enrollment in the APOLLO-B Phase 3 study in ATTR amyloidosis patients with cardiomyopathy.
Presented additional clinical data with patisiran – including 24-month results from the global open-label extension (OLE) study and results from an open-label study in patients with hATTR amyloidosis post-orthotopic liver transplant – and published findings from an evaluation of patisiran with concomitant or prior use of TTR stabilizers.
Advanced vutrisiran, a subcutaneously administered investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis.
Continued treating patients in the fully enrolled HELIOS-A Phase 3 study of vutrisiran in hATTR amyloidosis patients with polyneuropathy, and remain on track to report topline results in early 2021.
Continued enrollment in the HELIOS-B Phase 3 study in ATTR amyloidosis patients with cardiomyopathy.
Announced potential for a biannual dosing regimen option for vutrisiran, providing support for further product differentiation as a potential best-in-class agent.
Presented new interim data from the Phase 1/2 open-label extension (OLE) study of givosiran (the non-proprietary name for GIVLAARI) in acute hepatic porphyria (AHP).
Advanced lumasiran, an investigational RNAi therapeutic in development for the treatment of primary hyperoxaluria type 1 (PH1).
Received a positive CHMP opinion from EMA recommending approval of lumasiran for the treatment of PH1 in patients of all ages. If approved, lumasiran will be marketed in Europe under the brand name OXLUMO.
Received a positive scientific opinion from the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) through the Early Access to Medicines Scheme (EAMS).
Presented positive complete results from ILLUMINATE-B, a global Phase 3 pediatric study of lumasiran in PH1 patients less than six years of age, including infants, with preserved renal function.
Continued enrollment in the ILLUMINATE-C Phase 3 study of lumasiran for the treatment of advanced PH1 in patients of all ages.
Alnylam’s partner, Novartis, continued advancing inclisiran, potentially the first and only RNAi therapeutic cholesterol-lowering treatment. Inclisiran is undergoing regulatory review in the U.S. and EU.
Received a positive CHMP opinion from EMA recommending approval of inclisiran for the treatment of adults with hypercholesterolemia or mixed dyslipidemia. If approved, inclisiran will be marketed under the brand name LEQVIO.
Alnylam’s partner, Sanofi, continued advancement of the ATLAS Phase 3 program for fitusiran in patients with hemophilia A or B with and without inhibitors.
Advanced early- and mid-stage RNAi therapeutic pipeline programs.
Continued dosing in the Phase 1 study of ALN-AGT in hypertension.
In collaboration with Regeneron, advanced cemdisiran, an investigational RNAi therapeutic for the treatment of complement-mediated diseases.
Continued enrollment in a Phase 2 clinical trial of cemdisiran monotherapy in patients with IgA nephropathy, with topline results expected in 2021.
Alnylam’s partner Vir Biotechnology presented new data on VIR-2218 (ALN-HBV02) at the European Association for the Study of the Liver Digital International Liver Congress.
In addition, Vir initiated a Phase 2 combination trial of VIR-2218 with pegylated interferon-alpha (PEG-IFN-α), with initial clinical data anticipated in 2021.
The Company is announcing today that it has initiated dosing in a Phase 1 study of ALN-HSD, an investigational RNAi therapeutic targeting HSD17B13 in development for the treatment of nonalcoholic steatohepatitis (NASH). ALN-HSD is being advanced in collaboration with Regeneron.
The Company is announcing today that it will delay its planned filing of an IND for ALN-COV in order to obtain additional pre-clinical efficacy data in models of COVID-19 infection.
ALN-COV is part of a multi-target pre-clinical collaboration with Vir Biotechnology.
Continued progress with investigational RNAi therapeutics for CNS and ocular diseases, including advancement of ALN-APP, in development for the treatment of hereditary cerebral amyloid angiopathy (hCAA) and autosomal dominant Alzheimer’s Disease (ADAD), which remains on track for a CTA filing in mid-2021.
Regeneron exercised its co-development/co-commercialization option on the ALN-APP program, which Alnylam will lead.
Additional Business Updates
Barry Greene, former President of Alnylam, transitioned from Alnylam at the end of the third quarter. Yvonne Greenstreet assumed an expanded role as President and Chief Operating Officer on October 1, 2020.
Closed $150 million R&D funding component of the previously announced $2 billion strategic financing collaboration with Blackstone to accelerate the advancement of RNAi therapeutics.
Expanded global reach of commercialization activities with new third-party distribution agreement with taiba Middle East.
Received recognition from Science magazine as a top employer.
Upcoming Events
Alnylam announced today that it intends to present interim results from the Phase 1 trial of ALN-AGT at the American Heart Association Scientific Sessions 2020 on Friday, November 13.
The Company also announced today that it plans to present a review of its R&D and commercial activities at its upcoming R&D Day event being held virtually December 15 and 16.
In addition, in late 2020, Alnylam intends to:
Achieve regulatory approval for lumasiran in the EU and an FDA action for lumasiran in late 2020.
Alnylam’s partner Novartis expects regulatory approval for inclisiran in the EU and an FDA action for inclisiran in late 2020.
Achieve regulatory approval for ONPATTRO in Taiwan.
Alnylam’s partner Regeneron plans to initiate a Phase 1 study of cemdisiran in combination with pozelimab.
Financial Results for the Quarter Ended September 30, 2020
"The third quarter was very strong, with a rebound in ONPATTRO sales growth, particularly in the U.S., and continued impressive early performance with GIVLAARI. While the pandemic headwinds haven’t completely receded, we believe our teams have been very effective in meeting the needs of patients. As a result of this continued strength and our cautious optimism for the fourth quarter, we are again revising our full-year revenue guidance for ONPATTRO, increasing the range from $280-$300 million to $295-$310 million," said Jeff Poulton, Chief Financial Officer of Alnylam. "Beyond the commercial business, we also closed the $150 million R&D funding component of the Blackstone strategic financing collaboration, finalizing the last piece of a broad relationship that we believe secures our path to self-sustainability without the need for future equity offerings. Looking ahead, we believe we are well positioned to continue executing on our current commercial portfolio, with potential for two additional RNAi therapeutics coming to market, and advancing our broad pipeline of investigational programs to drive future growth."
Net product revenues were $99.2 million in the third quarter 2020 representing 115% growth from the third quarter 2019 primarily as a result of the addition of new patients on therapy and expansion into new markets for ONPATTRO, as well as the ongoing U.S. commercial launch and initial European launch of GIVLAARI.
Net Revenues from Collaborations
Net revenues from collaborations were $26.6 million in the third quarter 2020, an increase from $24.0 million in the third quarter 2019, primarily due to an increase in revenue recognized from our Vir collaboration.
Research & Development (R&D) and Selling, General & Administrative (SG&A) Expenses
R&D expenses were relatively flat on a GAAP basis and increased on a non-GAAP basis in the third quarter 2020 compared to the same period in 2019 primarily due to increased expenses associated with clinical and preclinical activities, personnel, and facilities as we continue to support our long-term strategic growth offset by decreased license fees associated with regulatory filings.
SG&A expenses increased in the third quarter 2020 compared to the same period in 2019 on a GAAP and non-GAAP basis primarily due to increased investment in commercial and medical affairs activity to support the ongoing launches of ONPATTRO and GIVLAARI and initial launch preparation activities for lumasiran. SG&A expenses on a GAAP basis also increased due to a change in estimate of contingent liabilities related to our arbitration with Ionis.
Cash and Investments
Cash, cash equivalents and marketable securities were $1.83 billion at the end of the third quarter 2020 compared to $1.54 billion at the end of 2019. The increase was primarily due to $600.0 million in proceeds received in the second quarter of 2020 from the sale of future royalties and issuance of common stock to Blackstone, partially offset by cash used in our operations to support overall growth.
A reconciliation of GAAP to non-GAAP results for the current quarter is included in the tables of this press release.
2020 Updated Financial Guidance
*Excludes $160-$180 million of expenses primarily related to stock-based compensation and a change in estimate of contingent liabilities from projected GAAP R&D and SG&A expenses.
The strategic financing collaboration with Blackstone under which Alnylam will receive up to $2 billion is expected to enable Alnylam’s achievement of a self-sustainable financial profile without need for future equity financings.
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 the press release are stock-based compensation expenses, unrealized gains on marketable equity securities, costs associated with our strategic financing collaboration, loss on contractual settlement and change in estimate of contingent liabilities. 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 unrealized gains on marketable equity securities, costs associated with our strategic financing collaboration, loss on contractual settlement and change in estimate of contingent liabilities because the Company believes these items are non-recurring transactions outside the ordinary course of the Company’s business.
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 third quarter 2020 results as well as expectations for the future via conference call on Thursday, November 5, 2020 at 8:30 am ET. To access the call, please dial 800-239-9838 (domestic) or +1-323-794-2551 (international) five minutes prior to the start time and refer to conference ID 6976021. 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 888-203-1112 (domestic) or +1-719-457-0820 (international) and refer to conference ID 6976021.
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). 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, visit ONPATTRO.com.
ONPATTRO Important Safety Information
Infusion-Related Reactions
Infusion-related reactions (IRRs) have been observed in patients treated with ONPATTRO (patisiran). In a controlled clinical study, 19% of ONPATTRO-treated patients experienced IRRs, compared to 9% of placebo-treated patients. The most common symptoms of IRRs with ONPATTRO were flushing, back pain, nausea, abdominal pain, dyspnea, and headache.
To reduce the risk of IRRs, patients should receive premedication with a corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers) at least 60 minutes prior to ONPATTRO infusion. Monitor patients during the infusion for signs and symptoms of IRRs. If an IRR occurs, consider slowing or interrupting the infusion and instituting medical management as clinically indicated. If the infusion is interrupted, consider resuming at a slower infusion rate only if symptoms have resolved. In the case of a serious or life-threatening IRR, the infusion should be discontinued and not resumed.
Reduced Serum Vitamin A Levels and Recommended Supplementation
ONPATTRO treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance (RDA) of vitamin A is advised for patients taking ONPATTRO. Higher doses than the RDA should not be given to try to achieve normal serum vitamin A levels during treatment with ONPATTRO, as serum levels do not reflect the total vitamin A in the body.
Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g. night blindness).
Adverse Reactions
The most common adverse reactions that occurred in patients treated with ONPATTRO were upper respiratory tract infections (29%) and infusion-related reactions (19%).
For additional information about ONPATTRO, please see the full Prescribing Information.
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 aminolevulinic acid synthase 1 (ALAS1) messenger RNA (mRNA), leading to reduction of toxins associated with attacks and other disease manifestations of AHP. For more information about GIVLAARI, visit GIVLAARI.com.
GIVLAARI Important Safety Information
Contraindications
GIVLAARI is contraindicated in patients with known severe hypersensitivity to givosiran. Reactions have included anaphylaxis.
Anaphylactic Reaction
Anaphylaxis has occurred with GIVLAARI treatment (<1% of patients in clinical trials). Ensure that medical support is available to appropriately manage anaphylactic reactions when administering GIVLAARI. Monitor for signs and symptoms of anaphylaxis. If anaphylaxis occurs, immediately discontinue administration of GIVLAARI and institute appropriate medical treatment.
Hepatic Toxicity
Transaminase elevations (ALT) of at least 3 times the upper limit of normal (ULN) were observed in 15% of patients receiving GIVLAARI in the placebo-controlled trial. Transaminase elevations primarily occurred between 3 to 5 months following initiation of treatment.
Measure liver function tests prior to initiating treatment with GIVLAARI, repeat every month during the first 6 months of treatment, and as clinically indicated thereafter. Interrupt or discontinue treatment with GIVLAARI for severe or clinically significant transaminase elevations. In patients who have dose interruption and subsequent improvement, reduce the dose to 1.25 mg/kg once monthly. The dose may be increased to the recommended dose of 2.5 mg/kg once monthly if there is no recurrence of severe or clinically significant transaminase elevations at the 1.25 mg/kg dose.
Renal Toxicity
Increases in serum creatinine levels and decreases in estimated glomerular filtration rate (eGFR) have been reported during treatment with GIVLAARI. In the placebo-controlled study, 15% of patients receiving GIVLAARI experienced a renally-related adverse reaction. The median increase in creatinine at Month 3 was 0.07 mg/dL. Monitor renal function during treatment with GIVLAARI as clinically indicated.
Injection Site Reactions
Injection site reactions were reported in 25% of patients receiving GIVLAARI in the placebo-controlled trial. Symptoms included erythema, pain, pruritus, rash, discoloration, or swelling around the injection site. One (2%) patient experienced a single, transient, recall reaction of erythema at a prior injection site with a subsequent dose administration.
Drug Interactions
Concomitant use of GIVLAARI increases the concentration of CYP1A2 or CYP2D6 substrates, which may increase adverse reactions of these substrates. Avoid concomitant use of GIVLAARI with CYP1A2 or CYP2D6 substrates for which minimal concentration changes may lead to serious or life-threatening toxicities. If concomitant use is unavoidable, decrease the CYP1A2 or CYP2D6 substrate dosage in accordance with approved product labeling.
Adverse Reactions
The most common adverse reactions that occurred in patients receiving GIVLAARI were nausea (27%) and injection site reactions (25%).
For additional information about GIVLAARI, please see full Prescribing Information.
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.