On February 15, 2024 Theratechnologies Inc. ("Theratechnologies" or the "Company") (TSX: TH) (NASDAQ: THTX), a biopharmaceutical company focused on the development and commercialization of innovative therapies, reported completion of enrollment of the first six participants in Part 3 of its Phase 1 clinical trial of sudocetaxel zendusortide in patients with advanced ovarian cancer (Press release, Theratechnologies, FEB 15, 2024, View Source [SID1234640154]). Sudocetaxel zendusortide, also known as TH1902, is an investigational, first-in-class peptide-drug conjugate (PDC) that targets the sortilin receptor (SORT1) and aims to expedite the internalization and delivery of the cytotoxic payload (docetaxel) directly into cancer cells.

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"Reaching this important milestone gives fresh momentum to the Phase 1 trial of sudocetaxel zendusortide, and to our overall oncology clinical development program," said Christian Marsolais, Ph.D., Senior Vice President and Chief Medical Officer at Theratechnologies. "As we gear up for the next round of screening, we look forward to adding patients at the next dose level and further characterizing the safety and efficacy of this novel peptide-drug conjugate."

Theratechnologies announced dosing of the first patient in Part 3 of the Phase 1 trial in October 2023. In June 2023, the U.S. Food and Drug Administration (FDA) accepted the Company’s amended protocol for the Phase 1 trial, which is designed to optimize the dosing, improve the therapeutic window and extend the duration of therapy of sudocetaxel zendusortide. The amendment, which the Company submitted in May 2023, also narrows the patient population to focus on individuals with high-grade serous ovarian cancer, including high-grade peritoneal or fallopian tube cancer, or high-grade endometrioid cancer — a population in which sudocetaxel zendusortide has demonstrated preliminary efficacy. After establishing the safety of the initial dose in the first six patients for a period of three months, the enrollment of the next cohort of six patients at a higher dose will be initiated.

"I am encouraged by the progress made in the Phase 1 trial of sudocetaxel zendusortide, from acceptance of the protocol amendment, to dosing the first patient, to completing enrollment of the first six women in this part of the study," commented Ira Winer, M.D., Ph.D., FACOG, Gynecologic Oncology and Phase I multidisciplinary member at Karmanos Cancer Center and trial investigator. "The ongoing study will yield important information about this agent’s utility in treating patients with platinum-resistant ovarian cancer, a population with few effective therapeutic options."

Parts 1 and 2 of the Phase 1 trial provided preliminary evidence of the antitumor activity of sudocetaxel zendusortide, as presented at the 2023 annual meeting of the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper). Details about the study design, participation criteria and contact information for the sites can be found at: View Source

About Sudocetaxel Zendusortide (TH1902) and SORT1+ Technology

Sudocetaxel zendusortide is a first-of-its-kind sortilin receptor (SORT1)-targeting PDC, and the first compound to emerge from the Company’s broader licensed oncology platform. A new chemical entity, sudocetaxel zendusortide employs a cleavable linker to conjugate (attach) a proprietary peptide to docetaxel, a well-established cytotoxic chemotherapeutic agent used to treat many cancers. The FDA granted Fast Track designation to sudocetaxel zendusortide as a single agent for the treatment of all sortilin-positive recurrent advanced solid tumors that are refractory to standard therapy. Sudocetaxel zendusortide is currently being evaluated in a Phase 1 clinical trial.

Theratechnologies has established the SORT1+ Technology platform as an engine for the development of PDCs that target SORT1, which is expressed in multiple tumor types. SORT1 is a "scavenger" receptor that plays a significant role in protein internalization, sorting, and trafficking. Expression of SORT1 is associated with aggressive disease, poor prognosis, and decreased survival. It is estimated that SORT1 is expressed in 40% to 90% of endometrial, ovarian, colorectal, triple-negative breast (TNBC), and pancreatic cancers, making this receptor an attractive target for anticancer drug development.

On February 15, 2024 Royalty Pharma plc (Nasdaq: RPRX) reported financial results for the fourth quarter and full year of 2023 and introduced full year 2024 guidance for Portfolio Receipts. "Royalty Pharma delivered outstanding results in 2023," said Pablo Legorreta, Royalty Pharma’s founder and Chief Executive Officer (Press release, Royalty Pharma , FEB 15, 2024, View Source [SID1234640151]).

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"We reported another year of strong growth in royalty receipts and deployed substantial capital in value-enhancing transactions, including our strongest year ever for synthetic royalty transactions. Furthermore, a number of positive clinical and regulatory milestones strengthened the outlook for our diversified royalty portfolio. Based on the strong fundamental tailwinds underpinning our business, our strong balance sheet and robust deal pipeline, I am confident we are in an excellent position to fund life sciences innovation and deliver attractive, long-term compounding growth."

Portfolio Receipts show strong growth for full year 2023

Portfolio Receipts (previously referred to as Adjusted Cash Receipts) decreased 31% to $736 million in the fourth quarter, reflecting the accelerated Biohaven payments received in the fourth quarter of 2022.

Portfolio Receipts increased 9% to $3,049 million for full year 2023, driven primarily by strong portfolio performance and new royalty acquisitions, and consistent with the raised guidance provided on January 8, 2024.

Royalty receipts grew 10% for the quarter and 8% for the full year.

Significant transaction activity in 2023 with eight potentially transformative therapies added to portfolio

Announced value of new transactions was $4.0 billion for full year 2023.

Transactions since 2020 expected to add approximately $1.2 billion to Portfolio Receipts in 2025.

Positive updates in the fourth quarter across development-stage royalty portfolio

Phase 3 results for Cytokinetics’ aficamten met the primary endpoint for hypertrophic cardiomyopathy.

Bristol Myers Squibb announced the acquisition of Karuna (marketer of KarXT for schizophrenia).

Phase 3 results for MorphoSys’ pelabresib met the primary endpoint in myelofibrosis; Novartis announced the acquisition of MorphoSys.

Financial guidance for full year 2024 (excludes contribution from future transactions)

Royalty Pharma expects 2024 Portfolio Receipts to be between $2,600 million and $2,700 million.

2024 Portfolio Receipts guidance includes expected growth in royalty receipts of 5% to 9%.

Financial & Liquidity Summary

Three Months Ended
December 31,

Twelve Months Ended
December 31,

(unaudited)

($ and shares in millions)

2023

2022

2023

2022

Portfolio Receipts

736

1,064

3,049

2,789

Net cash provided by operating activities

773

570

2,988

2,144

Adjusted EBITDA (non-GAAP)*

682

983

2,806

2,566

Portfolio Cash Flow (non-GAAP)*

687

996

2,708

2,421

Weighted average/fully diluted Class A ordinary shares outstanding

598

607

603

607

* See "Liquidity and Capital Resources" section. Adjusted EBITDA and Portfolio Cash Flow are non-GAAP liquidity measures calculated in accordance with the credit agreement. Portfolio Cash Flow is a non-GAAP measure that is calculated as Adjusted EBITDA minus interest paid or received, net.

Fourth Quarter 2023 Portfolio Receipts

As previously announced (January 8, 2024 press release), Portfolio Receipts is now being reported as a key performance metric. The calculation of Portfolio Receipts will result in the same amount as Royalty Pharma’s previous presentation of Adjusted Cash Receipts (which will no longer be reported).

This change of presentation will facilitate increased transparency into the economics of individual royalties as royalty receipts by product and franchise will now be reported net of legacy non-controlling interests. In addition, Royalty receipts and Milestones and other contractual receipts will be reported as two separate subtotals summing to Portfolio Receipts. This change will provide greater clarity on the underlying trends of Royalty Pharma’s royalty portfolio versus other contractual payments which may be more variable over time. Prior-period results using this updated presentation are available for download on the Quarterly Results page of the company’s website under Supplemental Financial Information (link here).

Portfolio Receipts Highlights

Three Months Ended December 31,

(unaudited)

($ in millions)

2023

2022

Change

Products:

Marketers:

Therapeutic Area:

Cystic fibrosis franchise

Vertex

Rare disease

208

187

11%

Tysabri

Biogen

Neuroscience

68

73

(7)%

Trelegy

GSK

Respiratory

60

47

28%

Imbruvica

AbbVie, Johnson & Johnson

Cancer

50

58

(13)%

Promacta

Novartis

Hematology

44

40

9%

Xtandi

Pfizer, Astellas

Cancer

38

38

1%

Tremfya

Johnson & Johnson

Immunology

35

29

21%

Evrysdi

Roche

Rare disease

20

14

44%

Cabometyx/Cometriq

Exelixis, Ipsen, Takeda

Cancer

18

15

18%

Spinraza

Biogen

Rare disease

17

—

n/a

Trodelvy

Gilead

Cancer

10

6

64%

Erleada

Johnson & Johnson

Cancer

9

5

72%

Orladeyo

BioCryst

Rare disease

8

6

29%

Nurtec ODT/Zavzpret

Pfizer

Neuroscience

5

4

20%

Other products(5)

63

71

(12)%

Royalty receipts

651

593

10%

Milestones and other contractual receipts

84

470

(82)%

Portfolio Receipts

736

1,064

(31)%

Results for full year 2023 and 2022 are shown in Table 4. Amounts shown in the table may not add due to rounding.

Portfolio Receipts was $736 million in the fourth quarter of 2023, a decrease of 31% compared to the same period in 2022. The decrease in the fourth quarter was attributable to the accelerated redemption of all outstanding Series A and Series B Biohaven Preferred Shares following Pfizer’s acquisition of Biohaven in October 2022, which is reflected within milestones and other contractual receipts. Royalty receipts increased 10%, primarily driven by growth in the cystic fibrosis franchise, Trelegy and Evrysdi, and the addition of new royalties on Spinraza. These positive factors were partially offset by declining royalty receipts on Imbruvica, Tysabri and other products.

Liquidity and Capital Resources

Royalty Pharma’s liquidity and capital resources are summarized below:

As of December 31, 2023, Royalty Pharma had cash and cash equivalents of $477 million and total debt with principal value of $6.3 billion.

Liquidity Summary

Three Months Ended
December 31,

Twelve Months Ended
December 31,

($ in millions)

2023

2022

2023

2022

Portfolio Receipts

736

1,064

3,049

2,789

Payments for operating and professional costs

(54)

(81)

(243)

(223)

Adjusted EBITDA (non-GAAP)*

682

983

2,806

2,566

Interest received/(paid), net

5

14

(98)

(145)

Portfolio Cash Flow (non-GAAP)*

687

996

2,708

2,421

Amounts may not add due to rounding.
*Adjusted EBITDA and Portfolio Cash Flow are calculated in accordance with the credit agreement.

Adjusted EBITDA and Portfolio Cash Flow are supplemental non-GAAP liquidity measures that are key components of certain material covenants contained in Royalty Pharma’s credit agreement.

Adjusted EBITDA (non-GAAP) was $682 million in the fourth quarter of 2023. Adjusted EBITDA is calculated in accordance with the credit agreement as Portfolio Receipts minus payments for operating and professional costs. The calculation of Adjusted EBITDA results in the same total as under Royalty Pharma’s previous presentation of Adjusted EBITDA.

Portfolio Cash Flow (non-GAAP) was $687 million in the fourth quarter of 2023. Portfolio Cash Flow is calculated in accordance with the credit agreement as Adjusted EBITDA minus interest paid or received, net. This non-GAAP measure was added to our disclosure to align with a material covenant contained in Royalty Pharma’s credit agreement. This measure reflects the cash generated by Royalty Pharma’s business that can be redeployed into value-enhancing royalty acquisitions, used to repay debt, returned to shareholders through dividends or share purchases or utilized for other discretionary investments. The calculation of Portfolio Cash Flow does not include development-stage funding payments – upfront and milestone. This is the primary material difference from Royalty Pharma’s previous presentation of Adjusted Cash Flow (which will no longer be reported).

Royalty Pharma has provided a reconciliation of each non-GAAP measure to the most directly comparable GAAP financial measure, net cash provided by operating activities in Table 5.

Royalty Pharma announced new transactions of up to $4.0 billion in 2023, which includes upfront payments and potential future milestones. Royalty Pharma is now providing an aggregate amount for total Capital Deployment, which reflects cash payments during the period for new and previously announced transactions. Capital Deployment was $1.0 billion in the fourth quarter and $2.2 billion in 2023. See the detail of Capital Deployment by category below.

Capital Deployment Details

Three Months Ended
December 31,

Twelve Months Ended
December 31,

($ in millions)

2023

2022

2023

2022

Acquisitions of financial royalty assets

(1,002)

(250)

(2,116)

(1,742)

Development-stage funding payments – upfront and milestone

—

(50)

(50)

(175)

Development-stage funding payments – ongoing

(1)

(1)

(2)

(2)

Purchases of available for sale debt securities

—

(86)

—

(480)

Milestone payments

—

—

(12)

—

Investments in equity method investees

(2)

—

(13)

(10)

Acquisitions of other financial assets

—

—

—

(21)

Contributions from legacy non-controlling interests – R&D

0

0

1

1

Total Capital Deployment

(1,005)

(386)

(2,192)

(2,428)

Amounts may not add due to rounding.

In October 2023, Royalty Pharma drew $350 million under its existing unsecured revolving credit facility, which was repaid during the fourth quarter of 2023. Royalty Pharma also executed an amendment to its credit agreement during the fourth quarter of 2023 to increase its borrowing capacity under the revolving credit facility to $1.8 billion and to extend the maturity for a portion of the commitments.

Royalty Pharma began repurchasing its Class A ordinary shares in April 2023 under a $1.0 billion multi-year share repurchase program. During the fourth quarter of 2023, Royalty Pharma repurchased approximately 957,000 shares for $26 million. The weighted-average diluted Class A ordinary shares outstanding for the fourth quarter of 2023 was approximately 598 million and the fully diluted Class A ordinary shares outstanding was approximately 607 million for the fourth quarter of 2022. Royalty Pharma repurchased approximately 10 million shares for $305 million in 2023 under this repurchase program.

Recent Transactions

During the fourth quarter of 2023, Royalty Pharma announced new transactions of up to $1.6 billion. Announced transactions amount reflects the entire amount of capital committed for new transactions during the year, including potential future milestones.

Recent transactions include:

In November 2023, Royalty Pharma acquired a royalty interest in long-acting injectable olanzapine (TEV-’749), a Phase 3 development-stage product for the treatment of schizophrenia, from Teva Pharmaceuticals Industries Ltd. (press release). Under the terms of the agreement, Royalty Pharma will provide R&D funding of up to $125 million to support the development of TEV-’749.

In October 2023, Royalty Pharma acquired additional royalties on Roche’s Evrysdi (press release), an approved product for the treatment of spinal muscular atrophy, from PTC Therapeutics, Inc. (PTC) for an upfront payment of $1.0 billion. Until December 31, 2025, PTC will have the option to sell the remainder of the Evrysdi royalty retained by PTC to Royalty Pharma for $500 million less royalties received in five equal tranches. If PTC exercises fewer than three of these options, Royalty Pharma has the option to purchase 50% of the remaining PTC royalty for $250 million less royalties received until March 31, 2026.

Additionally, in January 2024, Royalty Pharma acquired a royalty interest in ecopipam for an upfront payment of $49 million and up to $44 million in milestone payments contingent on the achievement of certain regulatory milestones. Ecopipam is in Phase 3 development by Emalex Biosciences for the treatment of Tourette Syndrome.

The information in this section should be read together with Royalty Pharma’s reports and documents filed with the SEC at www.sec.gov and the reader is also encouraged to review all other press releases and information available in the Investors section of Royalty Pharma’s website at www.royaltypharma.com.

Key Developments Relating to the Portfolio
The key developments related to Royalty Pharma’s royalty interests are discussed below based on disclosures from the marketers of the products.

Pelabresib

In February 2024, Novartis announced that it has entered into an agreement to make a voluntary public takeover offer to acquire MorphoSys at an offer price of €68.00 per share in cash, for a total equity value of €2.7 billion. The closing is expected in the first half of 2024.

In November 2023, MorphoSys announced positive topline results from the Phase 3 MANIFEST-2 study investigating pelabresib in combination with ruxolitinib compared with placebo plus ruxolitinib in JAK inhibitor-naive patients with myelofibrosis. A New Drug Application (NDA) is expected to be submitted to the U.S. Food and Drug Administration (FDA) in the second half of 2024.

Cystic fibrosis franchise

In February 2024, Vertex announced positive Phase 3 results from its new triple combination therapy for the treatment of cystic fibrosis (CF). Vertex plans to file for approval with global regulators for people with CF ages 6 years and older by mid-2024.

In November 2023, Vertex announced that the European Commission granted approval for the label expansion of Kaftrio in a combination regimen with ivacaftor for the treatment of children with CF ages 2 through 5 years old.

Trodelvy

In January 2024, Gilead announced that the Phase 3 EVOKE-01 study evaluating Trodelvy compared to docetaxel did not meet its primary endpoint of overall survival in patients with previously treated metastatic non-small cell lung cancer.

Aficamten

In December 2023, Cytokinetics announced positive topline results from SEQUOIA-HCM, the pivotal Phase 3 clinical trial of aficamten in patients with symptomatic obstructive hypertrophic cardiomyopathy. The full results will be presented at an upcoming conference.

KarXT

In December 2023, Bristol Myers Squibb announced it has agreed to acquire Karuna for $330 per share in cash, for a total equity value of $14.0 billion with an expected closing in the first half of 2024.

In November 2023, Karuna announced that the FDA accepted its NDA for KarXT for the treatment of schizophrenia with an FDA action date of September 26, 2024.

Skytrofa

In December 2023, Ascendis Pharma announced positive topline results from foresiGHt, its Phase 3 trial to compare TransCon hGH with placebo and daily hGH in adults with growth hormone deficiency. Ascendis plans to submit a supplemental Biologics License Application to the FDA in 2024.

Xtandi

In November 2023, Astellas and Pfizer announced that the companies received an approval by the FDA of a supplemental NDA for Xtandi for the treatment of patients with nonmetastatic castration-sensitive prostate cancer with biochemical recurrence at high risk for metastasis.

Trontinemab

In October 2023, Roche presented interim results of a Phase 1b/2a study for trontinemab, a novel brainshuttle Aβ antibody for the treatment of Alzheimer’s disease. This study demonstrated that trontinemab rapidly reduces amlyoid plaque reduction in patients with Alzheimer’s disease.

2024 Financial Outlook

Royalty Pharma has provided guidance for full year 2024, excluding transactions and borrowings announced after the date of this release, as follows:

Provided February 15, 2024

Portfolio Receipts

$2,600 million to $2,700 million

Payments for operating and professional costs

8% to 9% of Portfolio Receipts

Interest Paid

$160 million

The above Portfolio Receipts guidance includes expected royalty receipts growth of 5% to 9% in 2024.

Royalty Pharma’s full-year 2024 guidance reflects a negligible estimated foreign exchange impact to Portfolio Receipts, assuming current foreign exchange rates prevail for 2024.

Total interest paid is based on the semi-annual interest payment schedule of Royalty Pharma’s existing notes and is anticipated to be approximately $160 million in 2024. Interest paid is anticipated to be approximately $79 million in each of the first and third quarters of 2024 with de minimis amounts being recorded in the second and fourth quarters of 2024. The projection assumes no additional debt financing in 2024, including no drawdown on the revolving credit facility. In 2023, Royalty Pharma also collected interest of $72 million on its cash and cash equivalents, which partially offsets interest paid.

Royalty Pharma today provides this guidance based on its most up-to-date view on its prospects. This guidance assumes no major unforeseen adverse events and excludes the contributions from transactions announced subsequent to the date of this press release. Furthermore, Royalty Pharma may amend its guidance in the event it engages in new royalty transactions which have a material near-term financial impact on the company.

Financial Results Call

Royalty Pharma will host a conference call and simultaneous webcast to discuss its fourth quarter and full year 2023 results today at 8:00 a.m., Eastern Time. Please visit the "Investors" page of the company’s website at View Source to obtain conference call information and to view the live webcast. A replay of the conference call and webcast will be archived on the company’s website for at least 30 days.

On February 15, 2024 Intellia Therapeutics, Inc. (NASDAQ:NTLA), a leading clinical-stage gene editing company focused on revolutionizing medicine with CRISPR-based therapies, and ReCode Therapeutics, a clinical-stage genetic medicines company using tissue-specific delivery to power the next wave of mRNA and gene correction therapeutics, reported a strategic collaboration to develop novel genomic medicines for the treatment of cystic fibrosis (CF) (Press release, ReCode Therapeutics, FEB 15, 2024, View Source;utm_medium=rss&utm_campaign=intellia-therapeutics-and-recode-therapeutics-announce-strategic-collaboration-to-develop-novel-gene-editing-therapies-for-cystic-fibrosis [SID1234640149]). CF is a genetic disease caused by mutations in the CFTR gene, leading to the accumulation of thick mucus in the lungs, digestive systems and other organs. CF can result in life-threatening infections, respiratory failure and other serious complications.

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The collaboration will leverage Intellia’s proprietary CRISPR-based gene editing platform, including its DNA writing technology, and ReCode’s proprietary Selective Organ Targeting (SORT) lipid nanoparticle (LNP) delivery platform to precisely correct one or more CF disease-causing gene mutations. As part of the agreement, the companies will focus initial research efforts on therapeutic approaches that address CF for patients who have limited or no treatment options available, with the opportunity to expand the scope of the collaboration in later phases. Intellia will be responsible for the design of the editing strategy and research-grade components for the investigational therapies. ReCode will lead the subsequent preclinical and clinical development. ReCode will also lead worldwide commercialization for certain programs arising from the collaboration. Intellia will be eligible to receive pre-specified development and commercial milestone payments, as well as royalties on potential sales. Intellia may also exercise an option to lead commercialization in the U.S. for certain programs.

"Intellia’s vision to realize the full promise of gene editing includes extending the reach of our industry-leading CRISPR-based platform to targets outside the liver. This collaboration with ReCode is aimed at achieving that goal as we work together to accelerate the development of potentially life-changing therapies for people with cystic fibrosis," said Intellia President and Chief Executive Officer John Leonard, M.D. "Building on our CRISPR/Cas9 capabilities, we have made important progress advancing our proprietary DNA writing technology to enable a range of precise editing strategies. We are excited to combine our gene editing expertise and platform with ReCode’s novel lung-directed LNP delivery platform."

"We are excited to partner with Intellia, a clear leader in the gene editing space, with the ultimate goal of bringing life-altering therapies to CF patients," said ReCode Chief Executive Officer Shehnaaz Suliman, M.D. (MB ChB), M.B.A., M.Phil. "This collaboration provides further validation of ReCode’s SORT LNP platform to deliver diverse gene editing modalities to specific cells and tissues. By combining our highly synergistic technologies and capabilities, we are excited about the potential to enable a faster path for next-generation gene editing therapeutics to CF patients."

On February 15, 2024 Prothena Corporation plc (NASDAQ:PRTA), a late-stage clinical biotechnology company with a robust pipeline of investigational therapeutics built on protein dysregulation expertise, reported financial results for the fourth quarter and full year 2023 (Press release, Prothena, FEB 15, 2024, View Source [SID1234640148]). In addition, the Company provided 2024 financial guidance and business highlights.

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"2023 was a year of strong progress for Prothena as we advanced our protein dysregulation portfolio and moved closer to becoming a fully integrated commercial company. The next 12 to 18 months have the potential to transform Prothena with multiple upcoming clinical readouts across our robust portfolio," said Gene Kinney, Ph.D., President and Chief Executive Officer, Prothena. "We continue to advance our confirmatory Phase 3 AFFIRM-AL clinical trial for birtamimab and for PRX012 are evaluating multiple dose level cohorts in our ongoing Phase 1 clinical trial. In addition, we ended the year with IND clearances by the FDA for both PRX123 and PRX019, including Fast Track designation for PRX123. As we continue to grow our leadership at Prothena, we also appointed the founding, former Director of the FDA CDER Office of Neuroscience, Dr. Billy Dunn, to our board of directors. Dr. Dunn brings immeasurable regulatory and clinical development expertise, combined with a passion for helping patients, which will greatly benefit the millions of people affected by diseases caused by protein

dysregulation. Lastly, Prothena remains well financed with sufficient capital to ensure funding of activities beyond the completion of ongoing clinical trials."

2023 Business Highlights and Upcoming Milestones

Neurodegenerative Diseases Portfolio

Alzheimer’s Disease

PRX012, a wholly-owned potential best-in-class, next-generation subcutaneous antibody for the treatment of Alzheimer’s disease that targets a key epitope at the N-terminus of amyloid beta (Aβ) with high binding potency. The U.S. Food and Drug Administration (FDA) has granted Fast Track designation for PRX012 for the treatment of Alzheimer’s disease.
•Presented two preclinical studies at AD/PD in March 2023 and AAIC in July 2023 showing superior binding characteristics of PRX012
•Partnered with Walgreens in April 2023 to accelerate patient identification and recruitment for ongoing ASCENT-2 clinical trial
•Initial Phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) data supports once-monthly subcutaneous administration and ongoing evaluation in MAD cohorts
•Ongoing Phase 1 clinical trial continues as planned and expect to update in 2024

BMS-986446 (formerly PRX005), a potential best-in-class antibody for the treatment of Alzheimer’s disease that specifically targets a key epitope within the microtubule binding region (MTBR) of tau, a protein implicated in the causal pathophysiology of Alzheimer’s disease. BMS-986446 is part of a Global Neuroscience Research and Development Collaboration with Bristol Myers Squibb.
•Presented Phase 1 clinical trial SAD results in a poster presentation at AAIC in July 2023 showing that all three tested dose levels (low, medium, high) of PRX005 were considered generally safe and well tolerated, meeting the primary objective of this part of the clinical trial and supporting evaluation of doses in the ongoing MAD portion of this two-part clinical trial
•Bristol Myers Squibb paid $55 million for exclusive worldwide rights for PRX005 in July 2023 under the Global Neuroscience Research and Development Collaboration
•Bristol Myers Squibb will be responsible for future development, manufacturing, and commercialization of BMS-986446
•Bristol Myers Squibb reported that Phase 1 data supports moving BMS-986446 into a Phase 2 clinical trial in 1H 2024

PRX123, a wholly-owned potential first-in-class dual Aβ/tau vaccine designed for the treatment and prevention of Alzheimer’s disease, is a dual-target vaccine targeting key epitopes within the N-terminus of Aβ and MTBR-tau designed to promote amyloid clearance and block the transmission of pathogenic tau
•Presented preclinical results in a late breaker poster presentation at AAIC in July 2023 showing a PRX123 vaccine surrogate elicited robust antibody responses that bound with high avidity to Aβ plaques in Alzheimer’s disease brain tissue ex vivo and significantly reduced Aβ brain plaques
•Investigational new drug (IND) application cleared by FDA
•Fast Track designation granted by FDA
•Phase 1 timeline update expected in 2024

Parkinson’s Disease

Prasinezumab, a potential first-in-class antibody for the treatment of Parkinson’s disease that is designed to target key epitopes within the C-terminus of alpha-synuclein, and is the focus of a worldwide collaboration with Roche
•Roche completed enrollment for the Phase 2b PADOVA clinical trial in patients with early Parkinson’s disease in the first quarter of 2023
•Poster and oral presentations at AD/PD in March/April 2023 highlighted aspects of the Phase 2 PASADENA clinical trial of prasinezumab for the treatment of Parkinson’s disease
•Roche presented data at the International Congress of Parkinson’s Disease and Movement Disorders (MDS) from the open-label extension of the PASADENA clinical trial which shows that prasinezumab slowed the progression of motor deficits (MDS-UPDRS Part III OFF state score) in early-stage Parkinson’s disease
•Topline results from Phase 2b PADOVA clinical trial expected in 2024 (NCT04777331)

Neurodegenerative Diseases

PRX019, a potential treatment of neurodegenerative diseases with an undisclosed target, is part of a Global Neuroscience Research and Development Collaboration with Bristol Myers Squibb.
•IND application cleared by FDA in December 2023
•Phase 1 clinical trial timeline update expected in 2024

Rare Peripheral Amyloid Diseases Portfolio

AL Amyloidosis

Birtamimab, a wholly-owned potential best-in-class amyloid depleter antibody for the treatment of AL amyloidosis designed to directly neutralize soluble toxic light chain aggregates and promote clearance of amyloid that causes organ dysfunction and failure. Among patients with AL amyloidosis, a rare, progressive, and fatal disease, newly diagnosed individuals with advanced disease (e.g., Mayo Stage IV) are at the highest risk for early death. Birtamimab has been granted Fast Track designation by the FDA for the treatment of patients with Mayo Stage IV AL amyloidosis to reduce the risk of mortality and has been granted Orphan Drug Designation by both the FDA and European Medicines Agency. A significant survival benefit was observed in the post hoc analysis of birtamimab-treated patients categorized as Mayo Stage IV at baseline in the previous Phase 3 VITAL clinical trial (Blood 2023).
•Published Phase 3 VITAL clinical trial data in June 2023 in Blood, the peer-reviewed journal of American Society of Hematology (ASH) (Free ASH Whitepaper)
•The ongoing confirmatory Phase 3 AFFIRM-AL clinical trial in patients with Mayo Stage IV AL amyloidosis is being conducted under a Special Protocol Assessment (SPA) agreement with the FDA with a primary endpoint of all-cause mortality (time-to-event) at a significance level of 0.10
•Topline results from confirmatory AFFIRM-AL Phase 3 clinical trial expected between 4Q 2024 and 2Q 2025 (NCT04973137)

ATTR Amyloidosis

NNC6019 (formerly PRX004), a potential first-in-class amyloid depleter antibody for the treatment of ATTR cardiomyopathy designed to deplete the pathogenic, non-native forms of the transthyretin (TTR) protein and is being developed by Novo Nordisk as part of their up to $1.2 billion acquisition of Prothena’s ATTR amyloidosis business and pipeline

•Ongoing Phase 2 clinical trial in patients with ATTR cardiomyopathy is being conducted by Novo Nordisk;
•The Phase 2 clinical trial has fully recruited patients with topline data expected in 1H 2025 (NCT05442047)

2023 Organizational and Corporate Highlights

•Announced the appointment of Billy Dunn, M.D., founding, former Director of the FDA CDER Office of Neuroscience, to its Board of Directors

Fourth Quarter and Full Year of 2023 Financial Results
For the fourth quarter and full year of 2023, Prothena reported a net loss of $67.5 million and $147.0 million, respectively, as compared to a net income of $6.3 million and a net loss of $116.9 million for the fourth quarter and full year of 2022, respectively. Net loss per share was $1.26 and $2.76 for the fourth quarter of 2023 and for the full year of 2023, respectively, as compared to net income per share on a diluted basis of $0.12 and net loss per share of $2.47 for the fourth quarter and full year of 2022, respectively.
Prothena reported total revenue of $0.3 million and $91.4 million for the fourth quarter and full year of 2023, respectively, as compared to total revenue of $49.9 million and $53.9 million for the fourth quarter and full year of 2022, respectively. Total revenue for the fourth quarter and full year of 2023 included BMS collaboration revenue of $0.3 million and $91.3 million, respectively. The full year includes the $55 million option payment from BMS related to their exercise of their option to acquire the exclusive worldwide rights for BMS-986446, (formerly PRX005). This compares to total revenue for the fourth quarter of 2022 and the full year of 2022 that included BMS collaboration revenue of $9.9 million and $13.9 million, respectively and a $40.0 million milestone payment from Novo Nordisk related to the continued advancement of NNC6019 (formerly PRX004) in a Phase 2 clinical trial for the treatment of ATTR cardiomyopathy in the fourth quarter of 2022 and the full year of 2022.
Research and development (R&D) expenses totaled $61.9 million and $220.6 million for the fourth quarter and full year of 2023, respectively, as compared to $36.9 million and $135.6 million for the fourth quarter and full year of 2022, respectively. The increase in R&D expense for the fourth quarter and full year of 2023 compared to the same periods in the prior year was primarily due to higher clinical trial expenses, higher personnel related expenses, higher consulting and other R&D expenses. R&D expenses included non-cash share-based compensation expense of $5.0 million and $19.2 million for the fourth quarter and full year of 2023, respectively, as compared to $3.5 million and $14.8 million for the fourth quarter and full year of 2022, respectively.
General and administrative (G&A) expenses totaled $16.9 million and $61.8 million for the fourth quarter and full year of 2023, respectively, as compared to $13.1 million and $49.9 million for the fourth quarter and full year of 2022, respectively. The increase in G&A expenses for the fourth quarter and full year of 2023 compared to the same periods in the prior year was primarily related to higher personnel related and consulting expenses. G&A expenses included non-cash share-based compensation expense of $6.0 million and $21.7 million for the fourth quarter and full year of 2023, respectively, as compared to $3.9 million and $16.5 million for the fourth quarter and full year of 2022, respectively.
Total non-cash share-based compensation expense was $11.1 million and $40.9 million for the fourth quarter and full year of 2023, respectively, as compared to $7.4 million and $31.3 million for the fourth quarter and full year of 2022, respectively.

As of December 31, 2023, Prothena had $621.0 million in cash, cash equivalents and restricted cash, and no debt.
As of February 9, 2024, Prothena had approximately 53.7 million ordinary shares outstanding.

2024 Financial Guidance

The Company expects the full year 2024 net cash used in operating and investing activities to be $208 to $225 million and expects to end the year with approximately $405 million in cash, cash equivalents and restricted cash (midpoint). The estimated full year 2024 net cash used in operating and investing activities is primarily driven by an estimated net loss of $229 to $255 million, which includes an estimated $51 million of non-cash share-based compensation expense.

Conference Call Details

Prothena management will discuss these results and its 2024 financial guidance during a live audio conference call today, Thursday, February 15, 2024, at 4:30 PM ET. The conference call will be made available on the Company’s website at www.prothena.com under the Investors tab in the Events and Presentations section. Following the live audio webcast, a replay will be available on the Company’s website for at least 90 days.

To access the call via dial-in, please dial +1 (800) 715-9871 (U.S. and Canada toll free) or +1 (646) 307-1963 (international) five minutes prior to the start time and refer to conference ID number 1706941. A replay of the call will be available until February 22, 2024, via dial-in at +1 (800) 770-2030 (U.S. and Canada toll free) or +1 (609) 800-9909 (international), Conference ID Number 1706941.

On February 15, 2024 Prelude Therapeutics Incorporated (Nasdaq: PRLD), a clinical-stage precision oncology company, reported its financial results for the fiscal year ended December 31, 2023, and outlined key objectives for 2024 (Press release, Prelude Therapeutics, FEB 15, 2024, View Source [SID1234640147]).

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"In 2023, we prioritized and strengthened our pipeline to focus our resources on those programs that we believe have the highest likelihood of success and the greatest opportunity to deliver potentially safer and more effective therapies for patients that are currently underserved. We made significant progress with both our first-in-class IV SMARCA2 degrader compound, PRT3789, and our potentially best-in-class CDK9 inhibitor, PRT2527, which are on track to deliver meaningful initial proof-of-concept data in 2024," stated Kris Vaddi, Ph.D., Chief Executive Officer of Prelude.

Dr. Vaddi continued, "As evidence of our confidence in the potential therapeutic value of SMARCA2 to address a wide range of cancers with SMARCA4 mutations, we are also advancing our highly selective lead oral SMARCA2 degrader into Phase 1 clinical development in the second half of 2024. With both IV and oral molecules in the pipeline, we believe that we have the optionality to deliver the most appropriate treatment based on patient need and line of therapy and maintain our lead in this emerging new class of therapeutics.

"Our partnership with AbCellera represents a strategic step to expand our pipeline, based on our core competencies in medicinal chemistry, cancer biology and clinical development. The goal of the partnership is to create a portfolio of first-in-class precision ADCs that will utilize highly selective and potent small molecules and degrader payloads discovered by Prelude, coupled with highly differentiated antibodies from AbCellera. One of our first precision ADC programs utilizes a highly potent SMARCA degrader, which we expect will allow us to build on and extend the reach of our SMARCA programs."

Clinical Program Updates and Upcoming Milestones

SMARCA2 degrader PRT3789 on track to complete monotherapy dose escalation mid- year and initiate combination with docetaxel in first half of 2024; initial proof-of concept data expected in second half of 2024

PRT3789 is a potent and highly selective first-in-class SMARCA2 degrader, designed to be used in patients with a SMARCA4 mutation. Cancers with a SMARCA4 mutation represent a high unmet medical need. Patients with the SMARCA4 mutation have poor prognosis and, currently, no effective therapies.

PRT3789 is in Phase 1 clinical development in biomarker selected SMARCA4 mutant patients. To date, PRT3789 has completed the fifth dose escalation cohort and demonstrated selective, potent and dose dependent degradation of SMARCA2 with an acceptable safety profile. Based on PK/PD and safety data today, the Company expects to conclude monotherapy dose escalation mid-2024 and identify recommended Phase 2 dose(s). In addition, enrollment of patients into back-fill cohorts enriched for NSCLC and SMARCA4 loss-of-function mutations has been initiated. Objectives for this first Phase 1 clinical trial are to establish the safety and tolerability profile of PRT3789 as both monotherapy and in combination with docetaxel, evaluate efficacy, pharmacokinetics and pharmacodynamics and determine a dose and potential indications for advancement into a registrational clinical trial.

CDK9 inhibitor PRT2527 on track to complete monotherapy dose escalation mid-2024; initiate dosing in combination with zanubrutinib in first quarter of 2024; initial hematological proof-of-concept data expected in second half of 2024

PRT2527 is a potent and selective small molecule that has the potential to avoid off target toxicity and achieve greater clinical activity than other CDK9 programs currently in development. The Company is currently advancing PRT2527 as monotherapy in hematological indications such as B-cell malignancies and acute myeloid leukemia (AML) and has initiated the combination with zanubrutinib in B-cell malignancies.

PRT2527 is currently in Phase 1 clinical development and expected to complete monotherapy dose escalation in B-cell malignancies mid-year. A second cohort of patients with AML is expected to initiate in the first half of 2024.

Oral SMARCA2 degrader PRT7732 expected to enter Phase 1 clinical trial in the second half of 2024

Prelude’s discovery team has identified a series of highly selective and orally bioavailable SMARCA2 degraders. The lead oral molecule, PRT7732, is currently in investigational new drug (IND) enabling studies and on track to enter Phase 1 clinical development in the second half of 2024. PRT7732 is structurally distinct from PRT3789 and may provide clinically meaningful differences, more patient-friendly dosing and may be useful in earlier therapy lines.

Partnership with AbCellera expected to advance its first precision ADC

The AbCellera partnership, announced in November 2023, continues to progress towards the goal of delivering next-generation ADCs, combining AbCellera’s antibody discovery and development engine with Prelude’s expertise in medicinal chemistry and drug development. The partnership includes up to five precision ADC targets. Under the terms of the agreement, Prelude and AbCellera will jointly discover, develop, and commercialize products emerging from the collaboration. AbCellera will lead manufacturing activities and Prelude will lead clinical development and global commercialization, subject to AbCellera’s option to co-promote any resulting commercial products in the United States.

Full Year 2023 Financial Results

Cash and Cash Equivalents:

Cash and cash equivalents as of December 31, 2023 were $232.9 million. The Company anticipates that its existing cash, cash equivalents and marketable securities will fund Prelude’s operations into 2026.

Research and Development (R&D) Expenses:

R&D expenses for the year ended December 31, 2023 increased by $10.5 million to $103.4 million from $92.9 million for the year ended December 31, 2022. Included in research and development expenses for the year ended December 31, 2023 was $12.6 million of non-cash expense related to stock-based compensation expense, including employee stock options, compared to $11.5 million for the year ended December 31, 2022. The increase in research and development expenses was due to the timing of our clinical development programs along with an increase in non-cash stock-based compensation expense.

General and Administrative (G&A) Expenses:

G&A expenses for the year ended December 31, 2023 decreased by $1.8 million to $28.9 million compared to $30.7 million for the year ended December 31, 2022. Included in the general and administrative expenses for the year ended December 31, 2023 was $13.0 million of non-cash expense related to stock-based compensation expense, including employee stock options, as compared to $13.6 million for the same period in 2022. The decrease in general and administrative expenses was primarily due to our continued management of general and administrative expenses.

Net Loss:

Net loss for the year ended December 31, 2023 was $121.8 million or $2.02 per share, compared with a net loss of $115.4 million, or $2.44 per share, for the year ended December 31, 2022.