On February 15, 2024 Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, reported its consolidated financial results for the fourth quarter and full year ended December 31, 2023 and reviewed recent business highlights (Press release, Alnylam, FEB 15, 2024, View Source [SID1234640136]).

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"2023 was a year of strong execution at Alnylam. We delivered robust product revenue growth across our four wholly-owned commercial medicines, with $1.24 billion in global net product revenues, and achieved over 5,000 patients now being treated with an Alnylam commercial medicine. We also extended our leadership in RNAi with the first clinical demonstration of gene silencing in the human brain using an RNAi therapeutic, strengthened our business for the future through a landmark partnership with Roche and delivered solid financial performance," said Yvonne Greenstreet, MBChB, Chief Executive Officer of Alnylam. "Looking ahead to 2024, we are excited for a number of important milestones across the pipeline, including results from the HELIOS-B Phase 3 study of vutrisiran as well as the KARDIA-2 Phase 2 study of zilebesiran, and six clinical study starts. This progress sets us up for delivering on our Alnylam P5x25 goals of becoming a top-tier biotech company delivering sustained innovation and exceptional financial results."

Fourth Quarter 2023 and Recent Significant Corporate Highlights

Commercial Performance

Total TTR: ONPATTRO (patisiran) & AMVUTTRA (vutrisiran)

Achieved global net product revenues for ONPATTRO and AMVUTTRA for the fourth quarter of $79 million and $175 million, respectively, representing 10% total TTR quarterly growth compared to Q3 2023, and full year 2023 revenues of $355 million and $558 million, respectively, representing 40% total TTR annual growth compared to full year 2022.
Attained over 4,060 hATTR amyloidosis patients with polyneuropathy worldwide on commercial treatment with ONPATTRO or AMVUTTRA as of December 31, 2023.
Total Ultra-Rare: GIVLAARI (givosiran) & OXLUMO (lumasiran)

Achieved global net product revenues for GIVLAARI and OXLUMO for the fourth quarter of $59 million and $33 million, respectively, representing 11% total Ultra-Rare quarterly growth compared to Q3 2023, and full year 2023 revenues of $219 million and $110 million, respectively, representing 35% total Ultra-Rare annual growth compared to full year 2022.
Attained over 650 patients on commercial GIVLAARI and over 430 patients on commercial OXLUMO worldwide as of December 31, 2023.
R&D Highlights

Alnylam announces today updates to the statistical analysis plan for the HELIOS-B Phase 3 study of vutrisiran in patients with ATTR amyloidosis with cardiomyopathy. These will include updates to the primary and secondary endpoint structure, as well as study exposure. Topline results are expected to be available in late June or early July. Details will be discussed on the conference call this morning.

Published results from Phase 3 APOLLO-B study of patisiran in the New England Journal of Medicine.

Presented positive initial Phase 1 results with ALN-TTRsc04 demonstrating rapid knockdown achieved by a single dose with mean serum TTR reduction up to 97%, with durability supporting potential for annual dosing and an encouraging safety profile.

Presented positive results from the KARDIA-1 Phase 2 dose-ranging study of zilebesiran, an investigational RNAi therapeutic in development to treat hypertension patients at high cardiovascular risk, during the American Heart Association (AHA) Scientific Sessions.

Announces today that the U.S. Food and Drug Administration (FDA) has provided clearance to initiate the multiple-dose part (Part B) of the ongoing Phase 1 study of ALN-APP, an investigational RNAi therapeutic targeting amyloid precursor protein (APP) in development for the treatment of Alzheimer’s disease and cerebral amyloid angiopathy. The FDA has confirmed that multiple-dosing in the Phase 1 study may proceed at doses up to 180 mg given every six months, which covers all dose regimens planned to be explored in Part B. A partial clinical hold remains for higher or more frequent dosing regimens.

Reported updated positive interim results for the ongoing single ascending dose portion of the Phase 1 study of ALN-APP in patients with early-onset Alzheimer’s disease at the 2023 Alzheimer’s Association International Conference and at the 16th Clinical Trials in Alzheimer’s Disease conference.
Presented positive initial Phase 1 results with ALN-KHK demonstrating robust target engagement and an encouraging safety profile, supporting continued development as a novel treatment for type 2 diabetes mellitus.

Filed an Investigational New Drug (IND) application for ALN-BCAT, an investigational RNAi therapeutic targeting β-catenin in development for the treatment of hepatocellular carcinoma.

Sanofi presented positive results from the ATLAS-OLE Phase 3 extension study of fitusiran, demonstrating a substantially improved safety profile and consistent bleed protection in people with hemophilia A or B, with or without inhibitors. Specifically, the risk of thrombosis was reduced, with rates comparable to those reported in the general hemophilia population.

Sanofi expects to submit a New Drug Application (NDA) to the FDA in 2024.
Additional Business Updates

Ranked #1 on Boston Globe’s Top Places to Work list for 2023 in the "Largest Employer" category.
Recognized by Science magazine as a Top Employer for the fifth consecutive year.
Upcoming Events

Alnylam announces today that results from the KARDIA-2 Phase 2 study of zilebesiran will be presented in a Late-Breaker presentation at the American College of Cardiology Scientific Sessions 2024 on April 7, 2024 in Atlanta, Georgia.

In early 2024, Alnylam intends to:

Report topline results from the HELIOS-B Phase 3 study of vutrisiran in late June or early July.
Initiate the KARDIA-3 Phase 2 study of zilebesiran.
Initiate a Phase 2 study of ALN-APP in patients with cerebral amyloid angiopathy.
Initiate Part B of the Phase 1 study of ALN-KHK.
Initiate a Phase 1 study of ALN-BCAT.
Financial Highlights for the Fourth Quarter and Year End 2023

Three Months Ended
December 31,

Twelve Months Ended
December 31,

(In thousands, except per share amounts)

2023

2022

2023

2022

Net product revenues

$

346,288

$

261,675

$

1,241,474

$

894,329

Net revenue from collaborations

$

76,407

$

70,645

$

546,185

$

134,912

Royalty revenue

$

17,023

$

2,715

$

40,633

$

8,177

GAAP Operating loss

$

(116,404

)

$

(188,614

)

$

(282,175

)

$

(785,072

)

Non-GAAP Operating loss

$

(74,410

)

$

(145,847

)

$

(60,495

)

$

(554,423

)

GAAP Net loss

$

(137,870

)

$

(207,493

)

$

(440,242

)

$

(1,131,156

)

Non-GAAP Net loss

$

(96,643

)

$

(171,522

)

$

(201,618

)

$

(790,609

)

GAAP Net loss per common share – basic and diluted

$

(1.10

)

$

(1.68

)

$

(3.52

)

$

(9.30

)

Non-GAAP Net loss per common share – basic and diluted

$

(0.77

)

$

(1.39

)

$

(1.61

)

$

(6.50

)

For an explanation of our use of non-GAAP financial measures refer to the "Use of Non-GAAP Financial Measures" section later in this press release and for a reconciliation of each non-GAAP financial measure to the most comparable GAAP measures, see the table at the end of this press release.

Net Product Revenues

Three Months Ended
December 31,

Twelve Months Ended
December 31,

(In thousands)

2023

2022

2023

2022

ONPATTRO net product revenues

$

79,006

$

122,221

$

354,546

$

557,608

AMVUTTRA net product revenues

175,254

68,566

557,838

93,795

Total TTR net product revenues

254,260

190,787

912,384

651,403

GIVLAARI net product revenues

59,298

47,058

219,251

173,144

OXLUMO net product revenues

32,730

23,830

109,839

69,782

Total net product revenues

$

346,288

$

261,675

$

1,241,474

$

894,329

Year over Year % Growth

Three Months Ended
December 31, 2023

Twelve Months Ended
December 31, 2023

As Reported

At CER*

As Reported

At CER*

Total TTR net product revenues

33

%

31

%

40

%

40

%

GIVLAARI net product revenues

26

%

24

%

27

%

26

%

OXLUMO net product revenues

37

%

32

%

57

%

55

%

Total net product revenues

32

%

30

%

39

%

39

%

* CER = Constant Exchange Rate, representing growth calculated as if the exchange rates had remained unchanged from those used in 2022. CER is a non-GAAP measure.

Net product revenues increased 32% and 39% at actual currency during the three and twelve months ended December 31, 2023, respectively, compared to the same periods in 2022, and 30% and 39% at CER, respectively. The increases are primarily due to increased patients on our commercial TTR therapies driven by the launch of AMVUTTRA in the third quarter of 2022 as well as increased patients on GIVLAARI and OXLUMO therapies.
Net Revenues from Collaborations

Net revenues from collaborations increased 8% and 305% during the three and twelve months ended December 31, 2023, respectively, as compared to the same periods in 2022, primarily due to revenue recognized under our Collaboration and License Agreement with Roche, as executed in July 2023, and revenue recognized under our Novartis Collaboration Agreement associated with the achievement of specified commercialization and regulatory milestones.
Operating Expenses

Three Months Ended
December 31,

Twelve Months Ended
December 31,

(In thousands)

2023

2022

2023

2022

Cost of goods sold

$

71,975

$

46,172

$

268,216

$

140,174

Cost of goods sold as a percentage of net product revenues

20.8

%

17.6

%

21.6

%

15.7

%

Cost of collaborations and royalties

$

13,883

$

5,094

$

42,190

$

28,643

GAAP research and development expenses

$

272,141

$

262,039

$

1,004,415

$

883,015

Non-GAAP research and development expenses

$

253,056

$

245,095

$

907,142

$

790,854

GAAP selling, general and administrative expenses

$

198,123

$

210,344

$

795,646

$

770,658

Non-GAAP selling, general and administrative expenses

$

175,214

$

184,521

$

671,239

$

632,170

Cost of Goods Sold

Cost of goods sold as a percentage of net product revenues increased during the three and twelve months ended December 31, 2023, respectively, as compared to the same periods in 2022, primarily due to increased volume and rate of royalties payable on net sales of AMVUTTRA associated with tiered royalty percentages, in addition to increased excess and obsolete charges primarily due to canceling manufacturing commitments and the impairment of ONPATTRO inventory that had been manufactured for future demand associated with the ATTR amyloidosis with cardiomyopathy indication for patisiran for which we did not receive regulatory approval.
Research & Development (R&D) Expenses

GAAP and non-GAAP R&D expenses increased during the three and twelve months ended December 31, 2023, compared to the same periods in 2022, primarily due to increased headcount and infrastructure expenses to support our R&D pipeline, development expenses associated with the KARDIA-1 and KARDIA-2 zilebesiran Phase 2 studies, and manufacturing and research related expenses associated with our pre-clinical and developmental activities. GAAP R&D expenses further increased during the twelve month period due to increased stock-based compensation expense related to the accounting for certain performance-based awards during the period.
Selling, General & Administrative (SG&A) Expenses

GAAP and non-GAAP SG&A expenses decreased during the three months ended December 31, 2023, compared to the same period in 2022, primarily due to increased legal expenses in 2022 associated with the Patent Infringement Lawsuits we filed in March 2022 and the Department of Justice investigation, which closed in August 2023, and increased expenses in support of the global launch of AMVUTTRA in the third quarter of 2022.
GAAP and non-GAAP SG&A expenses increased during the twelve months ended December 31, 2023, compared to the same period in 2022, primarily due to increased headcount and other strategic investments in support of the global launch of AMVUTTRA and other expenses to support our strategic growth.
Other Financial Highlights

Cash, cash equivalents and marketable securities were $2.44 billion as of December 31, 2023, compared to $2.19 billion as of December 31, 2022, with the increase primarily due to the receipts of a $310 million upfront payment from Roche in connection with our partnership to co-develop and co-commercialize zilebesiran, a $100 million payment from Regeneron in connection with the achievement of certain criteria during early clinical development for our CNS program, ALN-APP, and nearly $150 million from employee option award exercises, offset by our operating loss for the year.
A reconciliation of our GAAP to non-GAAP results for the current quarter is included in the tables at the end of this press release.

2024 Financial Guidance

Full year December 31, 2024 financial guidance consists of the following:

Combined net product revenues for AMVUTTRA, ONPATTRO, GIVLAARI and OXLUMO1

$1,400 million – $1,500 million

Net Product Revenue Growth vs. 2023 at reported Fx rates1

13% – 21%

Net Product Revenue Growth vs. 2023 at constant exchange rates*

13% – 21%

Net revenues from collaborations and royalties

$325 million – $425 million

GAAP R&D and SG&A expenses

$1,900 million – $2,050 million

Non-GAAP R&D and SG&A expenses2

$1,675 million – $1,775 million

1 Uses January 31, 2024 FX rates including: 1 EUR = 1.08 USD and 1 USD = 147 JPY

2 Primarily excludes $225-$275 million of stock-based compensation expense from estimated GAAP R&D and SG&A expenses.

* CER = Constant Exchange Rate, representing growth calculated as if the exchange rates had remained unchanged from those used in the twelve months ended December 31, 2023. CER is a non-GAAP measure.

On February 15, 2024 Alkermes plc (Nasdaq: ALKS) reported financial results for the quarter and year ended Dec. 31, 2023 and provided financial expectations for 2024 (Press release, Alkermes, FEB 15, 2024, View Source [SID1234640135]).

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"We entered 2024 as a pure-play neuroscience company and are well positioned to deliver on our strategic priorities to drive growth of our proprietary commercial products, advance the clinical development of ALKS 2680 for the treatment of narcolepsy, and generate significant cash flow," said Richard Pops, Chief Executive Officer of Alkermes. "Our financial expectations for 2024 reflect our sharpened strategic focus and our work to position the business for sustained profitability and growth. As we look ahead, 2024 will be an important year as we focus on maintaining strong momentum in the launch of LYBALVI and advancing and expanding our development pipeline. We look forward to sharing our progress."

Key Financial Highlights

Revenues

(In millions)

Three Months Ended
December 31,

Twelve Months Ended
December 31,

2023

2022

2023

2022

Total Revenues

$

377.5

$

304.7

$

1,663.4

$

1,111.8

Total Proprietary Net Sales

$

242.0

$

216.1

$

920.0

$

777.6

VIVITROL

$

102.4

$

102.0

$

400.4

$

379.5

ARISTADAi

$

83.4

$

79.2

$

327.7

$

302.1

LYBALVI

$

56.2

$

34.9

$

191.9

$

96.0

Profitability

(In millions)

Three Months Ended
December 31,

Twelve Months Ended
December 31,

2023

2022

2023

2022

GAAP Net Income (Loss)

$

112.8

$

(28.3)

$

355.8

$

(158.3)

GAAP Net Income (Loss)
From Continuing Operations

$

160.6

$

17.2

$

519.2

$

(33.2)

Non-GAAP Net Income

$

37.4

$

24.2

$

243.7

$

57.9

Non-GAAP Net Income From
Continuing Operations

$

81.8

$

67.4

$

396.5

$

174.9

EBITDA

$

32.3

$

(1.2)

$

323.8

$

(84.0)

EBITDA From Continuing
Operations

$

72.8

$

34.6

$

486.3

$

50.6

Please refer to Note 2 below for details related to certain tax provisions recorded during the quarter ended Dec. 31, 2023 which impacted GAAP Net Income and Non-GAAP Net Income during the quarter.

Revenue Highlights

LYBALVI

– Revenues for the fourth quarter and year ended Dec. 31, 2023 were $56.2 million and $191.9 million, respectively.

– Fourth quarter revenues and total prescriptions grew 61% and 65%, respectively, compared to the fourth quarter of 2022.

ARISTADAi

– Revenues for the fourth quarter and year ended Dec. 31, 2023 were $83.4 million and $327.7 million, respectively.

– Fourth quarter revenues and total prescriptions (on a months of therapy basis) grew 5% and 4%, respectively, compared to the fourth quarter of 2022.

VIVITROL

– Revenues for the fourth quarter and year ended Dec. 31, 2023 were $102.4 million and $400.4 million, respectively.

Manufacturing & Royalties

– Royalty revenues from INVEGA SUSTENNA/XEPLION, INVEGA TRINZA/TREVICTA and INVEGA HAFYERA/BYANNLI for the fourth quarter and year ended Dec. 31, 2023 were $75.2 million and $486.1 million, respectively. 2023 royalty revenues included $195.4 million of back royalties and associated interest related to U.S. net sales of these products in 2022, following favorable resolution of the arbitration proceedings related to these products in the second quarter of 2023.

– VUMERITY revenues for the fourth quarter and year ended Dec. 31, 2023 were $33.6 million and $129.3 million, respectively.

Key Operating Expenses

Please see Note 1 below for details regarding discontinued operations.

(In millions)

Three Months Ended
December 31,

Twelve Months Ended
December 31,

2023

2022

2023

2022

R&D Expense –
Continuing Operations

$

73.9

$

73.0

$

270.8

$

272.7

R&D Expense –
Discontinued Operations

$

21.5

$

31.6

$

116.2

$

121.1

SG&A Expense –
Continuing Operations

$

169.8

$

152.9

$

689.8

$

590.8

SG&A Expense –
Discontinued Operations

$

19.4

$

4.7

$

48.6

$

15.0

Year-over-year increase in SG&A expense related to continuing operations was driven primarily by investment in the LYBALVI direct-to-consumer advertising campaign and certain one-time expenses related to the successful resolution of legal proceedings including the Janssen arbitration and VIVITROL patent litigation.

Balance Sheet

At Dec. 31, 2023, the company recorded cash, cash equivalents and total investments of $813.4 million, compared to $740.1 million at Dec. 31, 2022. The company’s total debt outstanding as of Dec. 31, 2023 was $290.7 million.

Share Repurchase Program
On Feb. 15, 2024, the company’s board of directors approved a new share repurchase program, authorizing the company to repurchase up to $400 million of the company’s ordinary shares (exclusive of any fees, commissions or other expenses related to such repurchases). The program does not have an expiration date and can be discontinued at any time. Please refer to Note 3 below for further details.

Financial Expectations for 2024
All line items are according to GAAP, except as otherwise noted.

In millions

2024
Expectations

Total Revenues a

$1,500 – $1,600

VIVITROL Net Sales

$410 – $430

ARISTADAi Net Sales

$340 – $360

LYBALVI Net Sales

$275 – $295

Cost of Goods Sold

$230 – $250

R&D Expenses

$225 – $255

SG&A Expenses

$625 – $655

GAAP Net Income b

$350 – $390

Non-GAAP Net Income b

$465 – $505

EBITDA

$445 – $485

Effective Tax Rate

~17%

a Expected Total Revenues reflect expiration of the U.S. royalty related to INVEGA SUSTENNA in August 2024.

b Expected 2024 weighted average basic share count of approximately 169.0 million shares outstanding and a weighted average diluted share count of approximately 173.0 million shares outstanding.

Recent Events

– In November 2023, the company completed the separation of its oncology business into Mural Oncology plc, a new, independent, publicly-traded company.

– In December 2023, the company announced that it had entered into a definitive agreement to sell its development and manufacturing facility in Athlone, Ireland to Novo Nordisk. Under the terms of the agreement, upon closing of the transaction, Alkermes will be entitled to a one-time cash payment of $92.5 million for the facility and related assets, subject to customary adjustments in accordance with the agreement. The transaction is expected to close in mid-2024, subject to certain closing conditions.

– In January 2024, the company announced topline results from a phase 3, open-label extension study assessing the long-term safety, tolerability and durability of treatment effect of LYBALVI in patients with schizophrenia, schizophreniform disorder or bipolar I disorder for up to four years of treatment, following treatment received in prior LYBALVI studies.

– In January 2024, the company announced that it had completed the narcolepsy type 1 cohort in its phase 1b study of ALKS 2680, the company’s novel, investigational orexin 2 receptor agonist in development for the treatment of narcolepsy. The data supported dose selection of 4 mg, 6 mg, and 8 mg once daily for the planned phase 2 study in narcolepsy type 1, which the company plans to initiate in the first half of 2024.

Notes and Explanations

1. The company determined that upon the separation of its oncology business, completed on Nov. 15, 2023, the oncology business met the criteria for discontinued operations in accordance with Financial Accounting Standards Board (FASB) Accounting Standards Codification (ASC) 205, Discontinued Operations. Accordingly, the accompanying consolidated financial statements for all periods presented have been updated to present the assets and liabilities associated with the oncology business as discontinued operations on the consolidated balance sheets, and the results of all discontinued operations reported as a separate component of loss in the consolidated statements of operations and comprehensive income (loss).

2. During the quarter ended Dec. 31, 2023, the company recorded a $102.2 million net tax benefit from continuing operations and an income tax provision of $6.9 million from discontinued operations driven by a $161.0 million tax benefit related to the partial release of a valuation allowance against certain Irish deferred tax assets, partially offset by

(i) an income tax expense related to a reduced foreign derived intangible income deduction following the publication of new guidance on the application of Section 174 of the U.S. Internal Revenue Code of 1986, as amended, and

(ii) a one-time charge related to the transfer of certain intellectual property in connection with the separation of the company’s oncology business.

The tax benefit related to the release of the valuation allowance was excluded from non-GAAP net income due to the one-time nature of the benefit.

3. Under the share repurchase program, the company may repurchase ordinary shares of the company from time to time in an aggregate amount of up to $400 million (exclusive of any fees, commissions or other expenses related to such repurchases), subject to general business and market conditions and other investment opportunities, through open market purchases, conducted through Rule 10b5-1 plans or 10b-18 plans pursuant to the Securities Exchange Act of 1934, as amended, or through other mechanisms permitted by the company’s constitution.

Conference Call
Alkermes will host a conference call and webcast presentation with accompanying slides at 8:00 a.m. EST (1:00 p.m. GMT) on Thursday, Feb. 15, 2024, to discuss these financial results and provide an update on the company. The webcast may be accessed on the Investors section of Alkermes’ website at www.alkermes.com. The conference call may be accessed by dialing +1 877 407 2988 for U.S. callers and +1 201 389 0923 for international callers. In addition, a replay of the conference call may be accessed by visiting Alkermes’ website.

On February 15, 2024 Agios Pharmaceuticals, Inc. (Nasdaq: AGIO), a leader in the field of cellular metabolism pioneering therapies for rare diseases, reported business highlights and financial results for the fourth quarter and year ended December 31, 2023 (Press release, Agios Pharmaceuticals, FEB 15, 2024, View Source [SID1234640134]).

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"The past 12 months have been remarkable for Agios. We reported positive data across our industry-leading pipeline of PK activators, including Phase 3 data in non-transfusion-dependent thalassemia, Phase 2 data in sickle cell disease and clinical proof-of-concept in lower-risk MDS, and expanded our preclinical pipeline by in-licensing a novel siRNA program from Alnylam," said Brian Goff, chief executive officer at Agios. "In 2024, we expect two additional Phase 3 readouts, including the Phase 3 study of mitapivat in transfusion-dependent thalassemia, and are actively preparing for a potential U.S. launch in thalassemia in 2025. Together with our strong cash position, Agios is poised for significant near- and long-term growth as we progress toward of our vision of becoming a leading rare disease company."

Fourth Quarter 2023 & Recent Highlights

PYRUKYND U.S. Launch: Generated $7.1 million in U.S. net revenue for the fourth quarter of 2023, a 4 percent decrease from the third quarter of 2023, primarily driven by lower customer inventory levels at the end of the fourth quarter of 2023, partially offset by favorable gross-to-net adjustments. A total of 178 unique patients have completed prescription enrollment forms, representing an increase of 11 percent over the third quarter of 2023. A total of 109 patients are on PYRUKYND therapy, a 9 percent increase from the third quarter of 2023.
Thalassemia: Announced positive topline data from the Phase 3 ENERGIZE study of mitapivat in non-transfusion-dependent thalassemia. The study achieved its primary endpoint of hemoglobin response and achieved both key secondary endpoints associated with change from baseline in FACIT-Fatigue Score and hemoglobin concentration.
Sickle Cell Disease: Presented positive results from the Phase 2 portion of the RISE UP pivotal study of mitapivat at the 65th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting and Exposition. The study achieved its primary endpoint of hemoglobin response and an improvement in annualized rates of sickle cell pain crises was observed.
Lower-risk Myelodysplastic Syndromes: Announced clinical proof-of-concept data in the open-label Phase 2a study of AG-946 for the treatment of anemia in lower-risk myelodysplastic syndromes (LR-MDS).
Earlier-stage Pipeline: Filed an Investigational New Drug Application (IND) for AG-181, Agios’ PAH stabilizer for the treatment of phenylketonuria (PKU).
Data presentations: Presented broad set of clinical and translational data at the 65th ASH (Free ASH Whitepaper) Annual Meeting & Exposition, including positive data from the Phase 2 portion of the RISE UP study of mitapivat in sickle cell disease, as noted above.
Anticipated 2024 Milestones

Thalassemia: Following the announcement of positive topline data from the Phase 3 ENERGIZE study of mitapivat in non-transfusion-dependent thalassemia in January 2024, Agios plans to report topline data from the Phase 3 ENERGIZE-T study of mitapivat in transfusion-dependent thalassemia (mid-year) and file for FDA approval of mitapivat in thalassemia (year-end)
Sickle Cell Disease: Complete enrollment in the Phase 3 portion of the RISE UP study of mitapivat (year-end)
Pediatric PK Deficiency: Complete enrollment in the Phase 3 ACTIVATE-kids study of mitapivat (mid-year). Report topline data from Phase 3 ACTIVATE kids-T study (year-end)
Lower-risk Myelodysplastic Syndromes: Dose first patient in Phase 2b study of AG-946 (mid-year)
Earlier-stage Pipeline: Dose the first patient in the Phase 1 study of AG-181 for the treatment of PKU (early 2024)
Fourth Quarter and Full Year 2023 Financial Results

Revenue: Net U.S. product revenue from sales of PYRUKYND was $7.1 million for the fourth quarter of 2023 compared to $4.3 million for the fourth quarter of 2022, and $26.8 million for the year ended Dec. 31, 2023 compared to $11.7 million for the year ended Dec. 31, 2022.

Cost of Sales: Cost of sales was $0.6 million for the fourth quarter of 2023 and $2.9 million for the full year ended Dec. 31, 2023.

Research and Development (R&D) Expenses: R&D expenses were $77.5 million for the fourth quarter of 2023 compared to $70.3 million for the fourth quarter of 2022, and $295.5 million for the year ended Dec. 31, 2023 compared to $279.9 million for the year ended Dec. 31, 2022. These changes reflect an increase in development costs for mitapivat and the up-front payment associated with the license agreement with Alnylam, partially offset by a reduction in expenses associated with the evolution of our research organization and the sale of our oncology business to Servier.

Selling, General and Administrative (SG&A) Expenses: SG&A expenses were $35.3 million for the fourth quarter of 2023 compared to $32.8 million for the fourth quarter of 2022, and $119.9 million for the year ended Dec. 31, 2023 compared to $121.7 million for the year ended Dec. 31, 2022.

Net Income (Loss): Net loss was $95.9 million for the fourth quarter of 2023 compared to a net income of $36.5 million for the fourth quarter of 2022, and net loss was $352.1 million for the year ended Dec. 31, 2023 compared to $231.8 million for the year ended Dec. 31, 2022. The increase in net loss is due to the $127.9 million sale to Sagard in the fourth quarter of 2022 of our rights to future contingent payments associated with royalties on U.S. net sales of TIBSOVO.

Cash Position and Guidance: Cash, cash equivalents and marketable securities as of Dec. 31, 2023, were $806.4 million compared to $1.1 billion as of Dec. 31, 2022. Agios expects that its cash, cash equivalents and marketable securities together with anticipated product revenue, interest income and vorasidenib milestone will enable the company to fund its operating expenses and capital expenditures at least into 2026. This does not include cash inflows which could extend runway beyond 2026 including potential royalties or monetization of royalties from vorasidenib, commercializing mitapivat outside of the U.S. through one or more partnerships, or other potential strategic business or financial agreements.

Conference Call Information
Agios will host a conference call and live webcast with slides today at 8:00 a.m. ET to discuss fourth quarter and full year 2023 financial results and recent business highlights. The live webcast can be accessed under "Events & Presentations" in the Investors section of the company’s website at www.agios.com. The archived webcast will be available on the company’s website beginning approximately two hours after the event.

On February 15, 2024 Imugene Limited (ASX: IMU), a clinical stage immuno-oncology company, reported that its CD19 oncolytic virotherapy drug candidate onCARlytics (on-CAR-19, CF33-CD19 HOV4), has dosed the first patient in the intravenous monotherapy arm of the Phase 1 clinical trial (Press release, Imugene, FEB 15, 2024, https://mcusercontent.com/e38c43331936a9627acb6427c/files/7ffe1327-a379-db3f-e3a1-90fed6834c49/Phase_1_onCARlytics_Trial_Doses_First_Intravenous_Patient.pdf [SID1234640107]).

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Known as OASIS, the first-in-class clinical trial is targeting adult patients with advanced or metastatic solid tumours. The trial aims to evaluate the safety and efficacy of two routes of administration, intratumoural (IT) injection and intravenous (IV) infusion, either alone, or in combination with blinatumomab.

The trial is titled: "A Phase I, Dose Escalation and Dose Expansion, Safety and Tolerability Study of onCARlytics (CF33-CD19), Administered Intravenously or Intratumorally in Combination with Blinatumomab in Adults with Advanced or Metastatic Solid Tumors." See View Source

The combination arm of the study will include onCARlytics combined with CD19 targeting bispecific monoclonal antibody blinatumomab (marketed as Blincyto by Amgen).

onCARlytics has the potential to target and eradicate solid tumours that otherwise cannot be treated with Blincyto therapy alone.

OASIS is a dose escalation trial being conducted in the United States, with the first IV patient dosed at City of Hope in California. Additional sites are expected to open for recruitment across the US with 52 patients proposed to take part in the trial.

Imugene Managing Director and CEO Leslie Chong said: "We’re pleased to see onCARlytics continue to advance in the clinic after the first patient on the trial was dosed in late October, and this move into intravenous administration marks another milestone in our mission to bring innovative cancer treatments to patients in need. With the combination arm of the study still to come, we eagerly await the chance to see more on the potential onCARlytics holds."

onCARlytics is a CD19-expressing oncolytic virus that enters tumour cells and forces them to express the CD19 protein on the cell surface, presenting a target for CD19 targeting therapies.

On February 14, 2024 Clarity Pharmaceuticals (ASX: CU6) ("Clarity", "the Company"), a clinical stage radiopharmaceutical company with a mission to develop next-generation products that improve treatment outcomes for children and adults with cancer, reported positive results from its diagnostic 64Cu-SAR-bisPSMA trial, COBRA (NCT05249127) (Press release, Clarity Pharmaceuticals, FEB 15, 2024, View Source [SID1234640087]).

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Dr Neal Shore MD, FACS Lead Principal Investigator in the COBRA trial, Medical Director of Carolina Urologic Research Centre, commented, "We are very enthusiastic regarding the data from the early phase COBRA trial as 64Cu-SAR-bisPSMA was confirmed to be safe and effective in detecting PC lesions in patients with BCR who came into the study with negative or equivocal scans using SOC imaging. The trial demonstrates a clinical advantage of same-day and next-day imaging in detecting additional lesions as well as for potentially detecting low prostate-specific membrane antigen (PSMA) expressing or smaller lesions. When detecting recurrence of PC, it is important to visualise small lesions, as reliable imaging of low volume tumor burden can affect treatment decision making. In the COBRA trial, we saw that 64Cu-SAR-bisPSMA positron emission tomography (PET) informed potential changes in the treatment plan in approximately half of the patients. This makes a difference for patients who may then have insight into the location of their disease recurrence and thereby proceed to treatment of their cancer. We look forward to additional data readouts from the trial and presenting the results at future international medical conferences. If the data from the COBRA trial can be substantiated in a registrational Phase 3 study, and if approved by the United States Food and Drug Administration (US FDA), this PET PSMA modality will impact care for patients with PC."

Clarity’s Executive Chairperson, Dr Alan Taylor, commented, "We are extremely excited with the initial findings from the COBRA trial as it further substantiates the many benefits of copper-64 (64Cu) and our optimised bisPSMA product in the diagnosis of PC. Combined with our clinical and pre-clinical trial data to date, this further validates SAR-bisPSMA as a potential best-in-class PSMA agent for the diagnosis (with 64Cu) and subsequent treatment (with copper-67 [67Cu]) of PC. We have also seen the performance of 64Cu-SAR-bisPSMA in the real-world setting through our compassionate use program, which demonstrated the ability of 64Cu-SAR-bisPSMA to detect lesions in patients with BCR and a negative or equivocal SOC imaging (including 18F-DCFPyL and 68Ga-PSMA-11). These cases also showed a higher number of lesions and lesions with higher maximum standardised uptake values (SUVmax) on next-day imaging. Therefore, we were already aware of the benefits of later-timepoint imaging, but the high number of lesions detected on same-day imaging that were negative or equivocal on SOC imaging (e.g. bone scan, CT or PSMA PET), and the almost doubling of the number of lesions with next-day imaging, is remarkable. The COBRA study now validates previous observations in a larger group of patients under trial conditions.

"Most importantly, the high rate of detection of PC in up to 80% of patients that were negative or equivocal on SOC imaging further brings to light the low sensitivity issues of current SOC imaging. We adhere to the highest standards and methods of clinical development as we pride ourselves on high quality science at Clarity. As such, the COBRA trial design was built to reflect the gold standard in clinical research and took a very conservative approach. Given we identified a large number of lesions with 64Cu-SAR-bisPSMA that were not visible with SOC scans, a number that was not anticipated when the protocol was prepared, it was not feasible nor ethical to verify all of these lesions with biopsy when caring for the patient. Therefore, our investigators were not able to confirm the true positivity of a very large number of lesions. Furthermore, among the patients that were excluded from the assessment of the efficacy endpoints because they had initiated systemic therapy while on study (which is not allowed according to the trial protocol), the majority had positive 64Cu-SAR-bisPSMA scans. As this was a first-in-human study in BCR PC patients, we have learnt significantly more about our product relative to current SOC imaging and will consider this potentially much higher level of detection and sensitivity of 64Cu-SAR-bisPSMA when structuring the Phase 3 trial design in this patient group.

"As can be seen from this study, and the clinicians reporting that they would change their treatment plan in response to this data, the increase in sensitivity with bisPSMA is incredibly important when assessing the return of PC in BCR patients. It is equally important for patients at initial staging of their disease, when they are considering their first course of definitive therapy, in order to understand whether their PC has metastasised or not from the primary lesion prior to prostatectomy. This is an immediate unmet medical need, which we are addressing with our Phase 3 CLARIFY trial2. Current SOC imaging fails to do this for a large percentage of men who eventually experience BCR of their PC. As such, there is an immediate opportunity for bisPSMA to address the entire market of PSMA imaging as we move closer to our ultimate goal of improving treatment outcomes of people with cancer.

"In addition to the clinical benefits, 64Cu-SAR-bisPSMA has a number of logistical and manufacturing advantages in comparison to other currently used PSMA agents. The ready-to-use product has been shipped to the trial sites in the US from a central manufacturing facility on-demand and on time, providing flexibility and reliability to the patients and their treating staff. This facilitates expanding the radiopharmaceutical field into the large oncology market, minimising logistical hindrances associated with the current generation of radio-diagnostics, and helping to focus on the needs of patients and their clinicians. Furthermore, the longer shelf-life of 64Cu-based products, coupled with the advantages of the SAR Technology, could offer access to PSMA PET for PC patients in underserved and broad geographical areas, which is one of the limitations of the approved PSMA agents due to their short half-life."

COBRA trial design & quality

The US-based COBRA study (Copper-64 SAR-bisPSMA in Biochemically Recurrent prostAte cancer) was a first-in-human trial of 64Cu-SAR-bisPSMA in patients with BCR of PC. It was a multi-centre, single-arm, non-randomised, Phase 1/2 diagnostic imaging study of 64Cu-labelled SAR-bisPSMA (64Cu-SAR-bisPSMA) administered to participants with BCR of PC following definitive therapy. The primary objectives of the trial were to investigate the safety and tolerability of 64Cu-SAR-bisPSMA as well as its ability to correctly detect recurrence of PC. Patients underwent PET/computed tomography (CT) scans on Day 0 and Day 1 (1-4h and 24±6h post-dose, respectively), which were interpreted by three blinded central readers. To determine the efficacy of 64Cu-SAR-bisPSMA imaging, the Day 0 and Day 1 PET/CT results of the central readers were assessed against a composite reference standard that was determined by an independent, blinded, central expert panel. The reference standard consisted of histopathology, follow-up SOC imaging and/or confirmed prostate specific antigen (PSA) response to focal therapy.

The design of the COBRA study followed advice from regulators to achieve the highest standards in clinical research in the BCR setting, in contrast to trials with other PSMA agents. Based on this guidance, the expert panel, who determined the reference standard, was blinded to the results of the 64Cu-SAR-bisPSMA scans and distinct from the central readers assessing the 64Cu-SAR-bisPSMA scans. This approach removed any potential biases in the assessment of the reference standard, which was not the case with previously approved PSMA tracers, where the reference standard was determined by readers having access to the PSMA scans investigated in the study, aiming to anatomically correlate the findings across the scans. Furthermore, a conservative approach was taken for the analysis of both co-primary endpoints. If a lesion identified on the 64Cu-SAR-bisPSMA scan was not biopsied and it was also not present on follow-up SOC imaging (a suboptimal reference standard with known low sensitivity), it was considered as false positive in the analysis by default. The higher standards in study design for COBRA compared to that used for other PSMA agents’ trials, along with various benefits intrinsic to 64Cu-SAR-bisPSMA not seen with currently approved products (e.g. higher uptake/retention and delayed imaging), make comparisons among other PSMA tracers and 64Cu-SAR-bisPSMA not viable. The methodology used in the COBRA trial underscores the ability of 64Cu-SAR-bisPSMA to correctly identify PC recurrence even when a higher level of rigour in study design is applied, making the transition of data to real world scenarios more probable.

Initial results from the COBRA trial

This study was the first-in-human trial of 64Cu-SAR-bisPSMA in patients with BCR of PC. Fifty-two patients with negative or equivocal SOC scans were enrolled and imaged, of whom 42 were included in the calculation of the efficacy endpoints. The median PSA at study entry was 0.9 ng/mL (range 0.25 – 17.60). This PSA range was considerably lower than in the registrational studies for the approved PSMA PET agents in BCR. Among the patients who did not complete the study as they proceeded to systemic therapy (which was not allowed according to the trial protocol), the majority had lesions identified on the 64Cu-SAR-bisPSMA scan, but they did not contribute towards the assessment of the efficacy endpoints. Results from COBRA showed for the first time that 64Cu-SAR-bisPSMA is safe and effective in detecting lesions in patients with BCR of PC who were negative or equivocal on SOC imaging (e.g. bone scan, CT or PET with approved PSMA imaging agents) at screening.

Next-day imaging – a key advantage

The possibility of performing next-day imaging is a feature not available to currently approved PSMA-targeted PET products and unique to 64Cu-based SAR diagnostics due to the optimal half-life of 64Cu and the ability of the SAR Technology to prevent leakage of copper isotopes from the radiopharmaceutical in-vivo. The COBRA trial confirmed the benefits of delayed imaging in this patient group as more lesions and more patients with a positive scan were identified on next-day imaging.

64Cu-SAR-bisPSMA was able to identify approximately 91% more lesions (median increase) on next-day imaging compared to same-day imaging (ranges across the readers for the total number of lesions: 53–80 on Day 0 vs. 82–153 on Day 1). The number of lesions in the pelvic LN region more than doubled on next-day imaging compared to same-day imaging (median increase of 108.3% across all readers comparing Day 0 vs. Day 1) (Figures 4 and 5). The ranges of CDR and patient-level detection rate (DR, defined as the proportion of participants with a positive 64Cu-SAR-bisPSMA PET/CT scan out of all scanned participants) were both higher on Day 1 compared to Day 0. The DR range on Day 0 was 44–58% (95% CI 30–71.8), increasing on Day 1 to 58–80% (95% CI 43.2–90).

About SAR-bisPSMA
SAR-bisPSMA derives its name from the word "bis", which reflects a novel approach of connecting two PSMA-targeting agents to Clarity’s proprietary sarcophagine (SAR) Technology that securely holds copper isotopes inside a cage-like structure, called a chelator. Unlike other commercially available chelators, the SAR Technology prevents copper leakage into the body. SAR-bisPSMA is a TCT that can be used with isotopes of copper-64 (Cu-64 or 64Cu) for imaging and copper-67 (Cu-67 or 67Cu) for therapy.

64Cu-SAR-bisPSMA and 67Cu-SAR-bisPSMA are unregistered products. The data outlined in this announcement has not been assessed by health authorities such as the US Food and Drug Administration (FDA). A clinical development program is currently underway to assess the efficacy and safety of these products. There is no guarantee that these products will become commercially available.

About Prostate Cancer
Prostate cancer is the second most common cancer diagnosed in men globally and the fifth leading cause of cancer death worldwide3. The American Cancer Institute estimates in 2024 there will be 299,310 new cases of prostate cancer in the US and around 35,250 deaths from the disease.