New Data Opens Potential for Patient Stratification for CriPec® Nanomedicines in Cancer and Other Indications via Non- Invasive Imaging

On May 4, 2022 Cristal Therapeutics, a Dutch pharmaceutical company developing tailored nanomedicines for the treatment of cancer and other diseases with high unmet patient need, reported the publication of the results of the clinical PICCOLO study in the peer-reviewed journal, Advanced Materials1 (Press release, Cristal Therapeutics, MAY 4, 2022, View Source [SID1234614016]).

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This first-of-its-kind study2, part funded by an EU Horizon 2020 and a Health Holland grant, applied radiolabelling and PET-imaging to non-invasively track CriPec nanomedicines in patients with solid tumours over time. The data showed that a diagnostic dose of CriPec nanomedicine radiolabelled with zirconium-89 (89Zr-CPC634) was reliably predictive for the behaviour of a therapeutic dose and provides a powerful tool to non-invasively monitor the biological journey, including tumour uptake. This opens up the potential of using this approach to stratify patients without exposing them to therapeutic dose levels and thus possible side effects.

In the study, undertaken in close collaboration with researchers from Amsterdam University Medical Centre (location VUmc), radiolabelled CriPec was followed by positron emission tomography / computed tomography (PET/CT) imaging in seven patients with solid tumours. A therapeutic dose as well as a diagnostic dose were administered, and pharmacokinetics and tumour uptake were assessed for both. Extended blood residence and substantial tumour uptake were observed and were in fact found to be comparable for both dose levels. These findings are significant as they provide further evidence for the long circulation and substantial tumour uptake of CriPec nanomedicines in patients, as was previously observed in other clinical studies2,3. They further support the potential for superior therapeutic performance of CriPec nanomedicines.

In addition, the ability to monitor CriPec nanoparticles in patients also provides Cristal Therapeutics with detailed information for use in its rational design process to engineer CriPec nanomedicines for superior therapeutic performance and to stratify patients for precision medicine-based approaches.

Dr Cristianne Rijcken, PharmD PhD, founder and CSO of Cristal Therapeutics said:

"Despite the many advances in the nanomedicine field, the heterogeneity of tumours, both inter- and intra-patient, remains a major challenge. The non-invasive, diagnostic approach validated in this unique study provides valuable insight into the behaviour of CriPec nanomedicines and gives Cristal Therapeutics a powerful tool to further enhance the rational design of our nanomedicines with the goal of stratifying patients for safer, more targeted anticancer treatments in the future."

Cristal Therapeutics is progressing a robust pipeline of nanoparticle therapeutic candidates which are rationally designed to target specific tissues, cells and intracellular components throughout the body. Its strategy is to partner its technology platforms and CriPec based therapeutic products to maximise the potential for advancing new medicines in areas of high unmet need.

Representatives from Cristal Therapeutics will be attending the BIO International Convention in San Diego 13-16 June 2022 – please contact [email protected].

About the PICCOLO study

In the PICCOLO clinical study, a docetaxel-entrapping polymeric nanoparticle was radiolabelled with zirconium-89 (89Zr-CPC634) and positron emission tomography / computed tomography (PET/CT) imaging was performed in seven patients with solid tumours of various origins with two different doses of CPC634: an on-treatment (containing 60 mg m-2 docetaxel) and a diagnostic (1-2 mg docetaxel) dose (NCT03712423). Pharmacokinetic half-life for 89Zr-CPC634 was mean 97.0 ±14.4 hours on-treatment, and 62.4 ±12.9 hours for the diagnostic dose (p = 0.003). At these doses accumulation was observed in 46% and 41% of tumour lesions with a median accumulation in positive lesions 96 hours post-injection of 4.94 and 4.45%IA kg-1 (p = 0.91), respectively.

Tetris Therapeutics raises US$15 million in seed funding to revolutionize targeted cancer treatments

On May 4, 2022 Singapore biotechnology startup Tetris Therapeutics reported that it has raised US$15 million from the funds managed by Trinity Innovation Bioventure Singapore (TIBS) and its affiliates to develop antibody drug conjugates (ADCs) that aim to address unmet medical needs (Press release, Axcynsis Therapeutics, MAY 4, 2022, View Source [SID1234618244]). ADCs are one of the fastest growing fields in cancer therapy with market size projected to grow at a compound annual growth rate of 24% over the period of 2022 to 2029. Global sales of currently marketed ADCs are forecast to exceed US$16.4 billion in 2026.

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"ADCs consist of three components, antibody, drug payload, and linker. We call ourselves Tetris Therapeutics because like the game of Tetris, different placement of the ADCs building blocks will result in distinct cancer treatment outcomes," said Dr. Zou Bin, founder and CEO of Tetris Therapeutics. "Although the first ADC dates back to the early 2000s, there is an urgent need to develop new generation of ADCs to further improve therapeutic window. We plan on harnessing the cell selectivity of antibodies and the cytotoxicity of small molecule toxins to selectively destroy malignant cancerous cells with a ‘magic bullet’ while sparing healthy tissues."

Established in March 2022, Tetris Therapeutics is a platform-based biotechnology company and firmly believes that ADC is the long-awaited solution to cancer. Funding from this seed round will be used to expand the team, establish the technology platform and develop a robust pipeline. Tetris Therapeutics is currently setting up research and development facilities in Singapore.

In addition to establishing Tetris Therapeutics, Dr. Zou is an adjunct associate professor at National University of Singapore and Nanyang Technological University. He is a serial entrepreneur and was the founder and CEO of Shanghai Blueray Biopharma. Under his leadership, he successfully led the team to develop several candidates into the investigational new drug (IND) stage. Prior to his venture, Dr. Zou started his career as a principal scientist at Novartis Institute for Tropical Disease and discovered Phase II clinical trial drug NITD609.

"Tetris Therapeutics is very grateful for the support of TIBS." Said Dr. Zou, "TIBS is a professional VC specializing in biotechnology investment. I am keen in working with TIBS and future investors to develop new medicines for cancer patients."

"TIBS is excited to invest in its first Singapore biotech." Said Dr. Thomas Keller, Investment Partner of TIBS, "Working with Dr. Zou Bin to nurture Tetris Therapeutics will be a wonderful journey and TIBS is looking forward to the rapid growth of Tetris Therapeutics."

Horizon Therapeutics plc Reports First-Quarter 2022 Financial Results

On May 4, 2022 Horizon Therapeutics plc (Nasdaq: HZNP) reported first-quarter 2022 financial results and maintained its full-year 2022 net sales and adjusted EBITDA guidance (Press release, Horizon Pharma, MAY 4, 2022, View Source [SID1234613475]).

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"Our first quarter financial and operational performance established a strong start to the year, with meaningful progress on our strategic priorities and positioning us well for another year of top-tier growth," said Tim Walbert, chairman, president and chief executive officer, Horizon. "We advanced our pipeline with the initiation of two clinical trials, drove strong performance of our key growth drivers, TEPEZZA, KRYSTEXXA and UPLIZNA, and continued our international expansion. In addition, the FDA granted priority review of our sBLA to expand the KRYSTEXXA label to include co-treatment of KRYSTEXXA plus methotrexate, marking an important milestone in our journey to help more uncontrolled gout patients benefit from the medicine."

First-quarter 2021 results were negatively impacted by a short-term TEPEZZA supply disruption due to U.S. government-mandated COVID 19-vaccine orders.

First Quarter and Recent Company Highlights

FDA Granted Priority Review of sBLA for Co-Treatment of KRYSTEXXA Plus Methotrexate: In March, the U.S. Food and Drug Administration (FDA) granted priority review of the Company’s sBLA to expand the label for KRYSTEXXA to include co-treatment with methotrexate. The Company submitted an sBLA in January based on results from the MIRROR Phase 4 randomized placebo-controlled trial which demonstrated that 71% of patients receiving KRYSTEXXA plus methotrexate achieved a complete response, a more than 30 percentage-point improvement compared to patients who were randomized to receive KRYSTEXXA plus placebo (p<0.0001). An updated label would allow the Company’s commercial team to promote KRYSTEXXA plus methotrexate to physicians. The Prescription Drug User Fee Act (PDUFA) action date is July 7, 2022.

UPLIZNA Approved in Europe and China for NMOSD: In April, the European Commission approved UPLIZNA for the treatment of adult patients with neuromyelitis optica spectrum disorder (NMOSD) who are Anti-Aquaporin-4 Immunoglobulin G Seropositive (AQP4-IgG+). Germany is expected to be the first country where the Company initiates promotional and commercialization efforts in the EU. In March, the Company’s strategic partner Hansoh Pharmaceutical Group Company Limited received approval of UPLIZNA for the treatment of NMOSD from the National Medical Products Administration of the People’s Republic of China.

Advancing the Company’s Global Expansion with TEPEZZA and UPLIZNA Launch Preparations in Brazil: The Company initiated its build-out of primary infrastructure in Brazil to support the potential approvals of TEPEZZA for thyroid eye disease (TED) and UPLIZNA for NMOSD. There are no on-label treatments that are commercially available for TED or NMOSD in Brazil. Brazil marks the newest market that the company is pursuing as part of its global expansion strategy.
Initiated Enrollment in Two Clinical Trials:

In January, the first patient enrolled in a pivotal Phase 2b trial to evaluate HZN-825 in patients with idiopathic pulmonary fibrosis (IPF), the most common form of interstitial lung disease. IPF is a rare, progressive lung disease caused by inflammation and fibrosis, or scarring, of the lungs.

In February, the first patient enrolled in a Phase 3 trial in Japan to evaluate TEPEZZA in patients with moderate-to-severe active TED, a serious, progressive and potentially vision-threatening rare autoimmune disease. TEPEZZA has not been approved for commercial use in Japan.
Announced Positive Topline Proof-of-Concept Data from Dazodalibep Rheumatoid Arthritis Trial: In May, the Company announced positive topline results from the Phase 2 randomized placebo-controlled trial of dazodalibep in patients with RA. The primary endpoint of the trial was met across all doses, a statistically significant change from baseline in DAS28-CRP, a standardized measure of disease activity in RA trials, at Day 113. In addition, dazodalibep was well tolerated across all doses. The impact observed after various doses will inform the dosing regimen for other studies with dazodalibep.

Presented New UPLIZNA Data at Key Medical Meetings: In April, multiple new data were presented at the American Academy of Neurology (AAN) 2022 Annual Meeting, including new data from the Phase 3 trial showing no significant differences in attacks or Expanded Disability Status Scale (EDSS) worsening between NMOSD patients treated with UPLIZNA with one pre-study attack and those with two or more pre-study attacks. A separate new analysis of the Phase 3 trial showed long-term treatment with UPLIZNA improved pain and quality of life outcomes for at least three years. Additionally, new data from the Phase 3 trial were presented at the 48th Annual Meeting of the North American Neuro-Ophthalmology Society (NANOS 2022) in February, showing that treatment with UPLIZNA effectively reduced the severity of attacks in patients with NMOSD.

Presented New TEPEZZA Data at Key Medical Meeting: In February, multiple new data were presented at NANOS 2022, including new data from a post-marketing safety analysis of hearing-related events associated with TEPEZZA. Among the thousands of patients included in the analysis, approximately 10% of all cases reported to the safety database included a hearing-related event. This rate was similar to the rate in the Company’s initial trials. The majority of hearing-related adverse events in the pivotal trials and post-approval have been mild to moderate and reversible. No new safety concerns were observed in the post-marketing safety analysis.

New TEPEZZA Chronic TED Data Published: In January, new data from an independent physician case study of six chronic TED patients who showed benefit after treatment with TEPEZZA were published in Eye, the official journal for the Royal College of Ophthalmologists. The case study adds to the growing body of evidence supporting the use of TEPEZZA in chronic TED patients, with nearly 60 chronic TED patients across multiple case studies who have demonstrated benefit.

Expanding East Coast R&D and Technical Operations Hub: In January, the Company announced it entered into an agreement to lease a new 192,000-square-foot, state-of-the-art facility under construction in Rockville, Maryland that will serve as the Company’s primary East Coast research and development and technical operations hub. The Company is significantly expanding and consolidating its East Coast footprint with the new facility, nearly quadrupling its current Maryland footprint acquired in the 2021 acquisition of Viela. The Company anticipates adding key R&D talent to support its growing research and development capabilities and expanded pipeline.

Received Multiple Best Workplace Awards: In April, the Company was named one of Fortune’s "100 Best Companies to Work For" for the second consecutive year, retaining the highest ranked position in the biotechnology/pharmaceutical category. In March, Great Place to Work Ireland recognized Horizon as one of the "Best Workplaces in Ireland 2022" for the third consecutive year. These recognitions add to the many workplace awards the Company has received, reflecting the high level of engagement of its employees.

New President, Global Commercial Operations: The Company announced today that Jacopo Leonardi will join Horizon as president, global commercial operations, reporting to Tim Walbert, chairman, president and chief executive officer, effective May 16, 2022. Leonardi is an accomplished life sciences executive with more than two decades of commercial experience, which includes commercial launch, R&D new product planning as well as accelerating growth for high performing businesses in rare disease and immunology. Leonardi will oversee the U.S. and international commercial organizations, commercial development (life-cycle management) and global medical affairs.
Key Clinical Development Programs

Daxdilimab (HZN-7734), an anti-ILT7 human monoclonal antibody that depletes certain dendritic cells. Depleting these cells may interrupt the cycle of inflammation that causes tissue damage in diseases such as lupus, and a variety of other autoimmune conditions.

Systemic Lupus Erythematosus (SLE) Trial: Phase 2 randomized placebo-controlled trial underway to evaluate daxdilimab in patients with SLE, a disease in which the body’s immune system attacks its own tissues and organs.

Alopecia Areata Trial: Phase 2 trial to evaluate daxdilimab in patients with alopecia areata, an autoimmune disorder characterized by nonscarring hair loss, expected to initiate in the second quarter of 2022.

Discoid Lupus Erythematosus (DLE) Trial: Phase 2 trial to evaluate daxdilimab in patients with DLE, a rare, chronic, inflammatory skin condition characterized by lesions that result in scarring, expected to initiate by mid-year 2022.

Lupus Nephritis Trial: Phase 2 trial to evaluate daxdilimab in patients with lupus nephritis, a rare, autoimmune and inflammatory condition of the kidney, expected to initiate in the third quarter of 2022.

Dermatomyositis Trial: Phase 2 trial to evaluate daxdilimab in patients with dermatomyositis, a rare, autoimmune disorder characterized by rashes, debilitating muscle weakness and interstitial lung disease, expected to initiate in the fourth quarter of 2022.
Dazodalibep (HZN-4920), a CD40 ligand antagonist that blocks T-cell interaction with CD40-expressing B-cells, disrupting the overactivation of the CD40 ligand co-stimulatory pathway. Several autoimmune diseases are associated with the overactivation of this pathway.

Sjögren’s Syndrome Trial: Phase 2 randomized placebo-controlled trial underway to evaluate dazodalibep in patients with Sjögren’s syndrome, a chronic, systemic autoimmune condition that impacts exocrine glands, including the salivary and tear glands. The trial completed enrollment in April 2022.

Rheumatoid Arthritis Trial: Phase 2 randomized placebo-controlled trial to evaluate dazodalibep in patients with RA. Topline results were announced in May 2022. The trial met the primary endpoint and dazodalibep was well tolerated.

Kidney Transplant Rejection Trial: Phase 2 open-label trial underway to evaluate dazodalibep in kidney transplant rejection patients.

Focal Segmental Glomerulosclerosis (FSGS) Trial: Phase 2 trial to evaluate dazodalibep in patients with FSGS, a rare kidney disorder characterized by scarring of glomeruli, expected to initiate in the fourth quarter of 2022.
HZN-825, an oral lysophosphatidic acid receptor 1 (LPAR1) antagonist designed to prevent gene activation.

Diffuse Cutaneous Systemic Sclerosis Trial: Pivotal Phase 2b trial underway to evaluate HZN-825 in diffuse cutaneous systemic sclerosis.

Idiopathic Pulmonary Fibrosis Trial: Pivotal Phase 2b trial initiated in January 2022 to evaluate HZN-825 in idiopathic pulmonary fibrosis, the most common form of interstitial lung disease.
UPLIZNA, an anti-CD19 humanized monoclonal antibody that depletes B-cells, including the pathogenic cells that produce autoantibodies.

Myasthenia Gravis Trial: Phase 3 randomized placebo-controlled trial underway to evaluate UPLIZNA in patients with myasthenia gravis, a chronic, rare, autoimmune neuromuscular disease that affects voluntary muscles, especially those that control the eyes, mouth, throat and limbs.

IgG4-Related Disease Trial: Phase 3 randomized placebo-controlled trial underway to evaluate UPLIZNA in patients with IgG4-related disease, which is a group of disorders marked by tumor-like swelling and fibrosis of affected organs, such as the pancreas, salivary glands and kidneys.
TEPEZZA, an insulin-like growth factor type 1 receptor (IGF-1R) antagonist monoclonal antibody.

Chronic TED Trial: Phase 4 randomized placebo-controlled trial underway to evaluate TEPEZZA in chronic TED.

TED in Japan (OPTIC-J) Trial: Phase 3 randomized placebo-controlled trial in Japan initiated in February 2022 to evaluate TEPEZZA in patients with moderate-to-severe active TED.

Subcutaneous (SC) Administration Trial: Phase 1b trial to explore the pharmacokinetics, safety, tolerability, efficacy and immunogenicity of subcutaneous administration of TEPEZZA in patients with TED, expected to initiate by mid-year 2022.

Diffuse Cutaneous Systemic Sclerosis Exploratory Trial: Phase 1 exploratory trial underway to evaluate TEPEZZA in diffuse cutaneous systemic sclerosis.
KRYSTEXXA, a recombinant uricase enzyme that converts urate into a water-soluble liquid, allantoin, that can be easily excreted from the body.

Shorter Infusion Duration Trial: Phase 4 open-label trial underway to evaluate the impact of administering KRYSTEXXA plus methotrexate over a shorter infusion duration in patients with uncontrolled gout.

Monthly Dosing Trial: Phase 4 open-label trial underway to evaluate monthly dosing of KRYSTEXXA plus methotrexate in patients with uncontrolled gout.

Retreatment Trial: Phase 4 open-label trial underway to evaluate KRYSTEXXA plus methotrexate in patients who were not complete responders to KRYSTEXXA monotherapy.
HZN-1116, a fully human monoclonal antibody designed to bind and neutralize the function of the FLT3-ligand, thereby reducing both conventional and plasmacytoid dendritic cells.

Autoimmune Disease Trial: Phase 1 trial underway to evaluate HZN-1116 in patients with autoimmune diseases.
First-Quarter Financial Results

Note: For additional detail and reconciliation of non-GAAP financial measures to the most directly comparable GAAP financial measures, please refer to the tables at the end of this release.

Net Sales: First-quarter 2022 net sales were $885.2 million, an increase of 159% compared to the first quarter of 2021. First-quarter 2021 results were negatively impacted by a short-term TEPEZZA supply disruption due to U.S. government-mandated COVID 19-vaccine orders.

Gross Profit: Under U.S. GAAP, the first-quarter 2022 gross profit ratio was 75.7% compared to 70.7% in the first quarter of 2021. The non-GAAP gross profit ratio in the first quarter of 2022 was 88.9% compared to 90.9% in the first quarter of 2021.

Operating Expenses: R&D expenses were 11.7% of net sales and SG&A expenses were 42.1% of net sales in the first quarter of 2022. First-quarter non-GAAP R&D expenses were 10.4% of net sales and non-GAAP SG&A expenses were 37.1% of net sales.

Income Tax Expense (Benefit): On a GAAP basis in the first quarter of 2022, income tax benefit was $31.5 million. First-quarter non-GAAP income tax expense was $35.7 million.

Net Income: In the first-quarter of 2022, net income on a GAAP and non-GAAP basis was $204.3 million and $315.8 million, respectively.

Earnings (Loss) per Share: On a GAAP basis, diluted earnings (loss) per share in the first quarter of 2022 and 2021 were $0.87 and $(0.55). Non-GAAP diluted earnings per share in the first quarter of 2022 and 2021 were $1.34 and $0.02, respectively. Weighted average shares outstanding used for calculating GAAP and non-GAAP diluted earnings per share in the first quarter of 2022 were 236.0 million.
First-Quarter Segment Results

Management uses net sales and segment operating income to evaluate the performance of the Company’s two segments, the orphan segment and the inflammation segment. While segment operating income contains certain adjustments to the directly comparable GAAP figures in the Company’s consolidated financial results, such as the exclusion of upfront and milestone payments related to license and collaboration agreements, it is considered to be prepared in accordance with GAAP for purposes of presenting the Company’s segment operating results.

Orphan Segment Operating Income

First-quarter 2021 results were negatively impacted by a short-term TEPEZZA supply disruption due to U.S. government-mandated COVID 19-vaccine orders.

UPLIZNA was acquired on March 15, 2021. First-quarter 2022 UPLIZNA net sales included $5.2 million in revenue and milestone payments from the Company’s international partners.

First-quarter 2022 net sales of the orphan segment, the Company’s strategic growth segment, were $834.4 million, driven by the strong performance of TEPEZZA, KRYSTEXXA, RAVICTI, PROCYSBI, ACTIMMUNE and UPLIZNA. First-quarter 2022 orphan segment operating income was $351.5 million.

Inflammation Segment Operating Income


On Aug. 4, 2021, Alkem Laboratories, Inc. initiated an at-risk launch of generic DUEXIS in the United States.

First-quarter 2022 net sales of the inflammation segment were $50.9 million and segment operating income was $15.3 million.
Cash Flow Statement and Balance Sheet Highlights

First-quarter 2022 operating cash flow on a GAAP and non-GAAP basis was $215.8 million and $222.6 million, respectively.

As of March 31, 2022, the Company had cash and cash equivalents of $1.64 billion.

As of March 31, 2022, the total principal amount of debt outstanding was $2.60 billion.
2022 Guidance

The Company continues to expect full-year 2022 net sales to range between $3.9 billion and $4.0 billion, representing 22% growth at the midpoint. The Company continues to expect TEPEZZA full-year 2022 net sales percentage growth in the mid-30s and KRYSTEXXA full-year 2022 net sales growth of more than 20%. The Company continues to expect full-year 2022 adjusted EBITDA to range between $1.63 billion and $1.70 billion, representing 30% growth and 230 basis points of margin expansion at the midpoint.

Webcast

At 8 a.m. EDT / 1 p.m. IST today, the Company will host a live webcast to review its financial and operating results and provide a general business update. The live webcast and a replay may be accessed at View Source Please connect to the Company’s website at least 15 minutes prior to the live webcast to ensure adequate time for any software download that may be needed to access the webcast. A replay of the webcast will be available approximately two hours after the live webcast.

Ionis reports first quarter financial results and recent business achievements

On May 4, 2022 Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) reported financial results for the first quarter of 2022 and recent business achievements (Press release, Ionis Pharmaceuticals, MAY 4, 2022, View Source [SID1234613507]).

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"We are off to a strong start this year highlighted by progress in our rich late- and mid-stage pipeline. We remain on track for data from the NEURO-TTRansform study of eplontersen in patients with hereditary ATTR polyneuropathy by mid-year. Assuming positive data, we plan to file for regulatory approval by the end of this year. We recently increased the size and duration of our CARDIO-TTRansform study of eplontersen in patients with ATTR cardiomyopathy. Our aim is to generate even more robust data and ensure a highly positive study outcome to successfully compete in this growing and dynamic market," said Brett P. Monia, Ph.D., chief executive officer of Ionis. "We also reported positive data from two potential best-in-class medicines. In the Phase 2b ETESIAN study, ION449, our investigational medicine targeting PCSK9, demonstrated robust LDL-C and PCSK9 reductions in statin-treated patients with hypercholesterolemia. ION449 was generally well tolerated in this study. Additional positive data from the Phase 2 study of donidalorsen demonstrated significant improvements in quality of life in people with hereditary angioedema. Looking ahead, we expect to provide additional key mid-stage data readouts and updates on our technology advancements. These upcoming catalysts, together with our recent achievements, position us well to continue to drive substantial growth and value for all stakeholders."

First Quarter 2022 Summary Financial Results

On track to achieve 2022 financial guidance, based on the following first quarter results:

$142 million in total revenues
$173 million of operating expenses on a non-GAAP basis(1) and $199 million on a GAAP basis
$39 million net loss on a non-GAAP basis(1) and $65 million on a GAAP basis
$2.1 billion of cash and short-term investments
"A key element of Ionis’ financial strength is our ability to generate substantial revenue from multiple diverse sources on a sustained basis. Our first quarter financial results in which revenues grew more than 25 percent year over year were an excellent example of this. We generated revenues from our marketed products, including SPINRAZA, and from numerous partnered medicines as they advanced. Our first quarter financial results also reflect our investments in our rich late-stage pipeline and in activities to prepare for our launches of eplontersen, olezarsen and donidalorsen," said Elizabeth L. Hougen, chief financial officer of Ionis. "We are on track to meet our 2022 financial guidance. With $2.1 billion of cash, we are well capitalized with the resources we need to continue investing in our large agenda to drive substantial future growth."

Recent Marketed Products Highlights

SPINRAZA: the global market leader for the treatment of spinal muscular atrophy (SMA) patients of all ages

$473 million in worldwide SPINRAZA sales in the first quarter
Biogen provided updates from the ASCEND, RESPOND and NURTURE studies of SPINRAZA at the Muscular Dystrophy Association (MDA) Clinical and Scientific conference and the American Academy of Neurology (AAN) annual meeting
TEGSEDI and WAYLIVRA: important medicines approved for the treatment of patients with polyneuropathy caused by hereditary TTR amyloidosis and familial chylomicronemia syndrome, respectively

Continued to progress into new and existing markets in Europe and Latin America in the first quarter through Swedish Orphan Biovitrum AB (Sobi) and PTC Therapeutics, respectively
First Quarter 2022 and Recent Events

Advancing Ionis’ near-term commercial opportunities toward the market

Increased study size and duration in the Phase 3 CARDIO-TTRansform study of eplontersen in patients with ATTR cardiomyopathy with the aim to generate even more robust data and ensure a highly positive study outcome to successfully compete in this growing and dynamic market. Data from this study are expected in the first half of 2025
The U.S. FDA granted orphan drug designation to eplontersen for the treatment of patients with ATTR
Published positive data from the Phase 2 study of olezarsen in patients with hypertriglyceridemia and either at high risk for or with established cardiovascular disease in the European Heart Journal
Initiated a study of olezarsen in patients with hypertriglyceridemia to support the broad Phase 3 program
Published positive data from the Phase 2 study of donidalorsen in patients with hereditary angioedema (HAE) in the New England Journal of Medicine
Presented additional positive data from the Phase 2 study of donidalorsen in patients with HAE at the American Academy of Allergy, Asthma and Immunology (AAAAI) annual meeting
Advancing Ionis’ leading cardiovascular disease franchise

AstraZeneca presented positive data from the Phase 2b ETESIAN study of ION449 (AZD8233) targeting PCSK9 in statin treated patients with dyslipidemia at the American College of Cardiology (ACC) annual scientific session
Achieved full enrollment in the Phase 2b study of IONIS-AGT-LRx in patients with treatment-resistant hypertension, with data expected in the second half of 2022
Advancing Ionis’ leading neurological disease franchise

Roche plans to initiate a new Phase 2 study of tominersen in patients with Huntington’s disease based on findings from a post-hoc analysis of the GENERATION-HD1 study
Biogen initiated a Phase 1/2 study of ION260 (BIIB132) targeting ataxin-3 (ATXN3) in patients with spinocerebellar ataxia type 3 (SCA3), resulting in an $8 million milestone payment from Biogen
Biogen advanced the Phase 1/2 study of ION859 (BIIB094) targeting LRRK2 in patients with Parkinson’s disease, resulting in a $10 million milestone payment from Biogen
Announced the discontinuation of IONIS-C9Rx (BIIB078) due to lack of patient benefit demonstrated in the Phase 1/2 study in patients with C9orf72-ALS
2022 Pipeline Milestones(2)

Anticipated 2022 Regulatory Updates

Program

Anticipated Indication

Regulatory Action

H1

H2

Eplontersen

ATTRv polyneuropathy

NDA filing

Anticipated Key 2022 Data Readouts

Program

Data Readout

Anticipated Indication

H1

H2

Tominersen

Phase 3 post hoc

Huntington’s disease

ION449 (PCSK9)

Phase 2b (ETESIAN)

Cardiovascular disease

Donidalorsen

Phase 2

HAE

IONIS-C9Rx (BIIB078)

Phase 1/2

C9-ALS

Tofersen

Phase 3 OLE

SOD1-ALS

Eplontersen

Phase 3

ATTRv polyneuropathy

IONIS-AGT-LRx

Phase 2b

Treatment-resistant hypertension

Fesomersen (FXI)

Phase 2b

Thrombosis

Bepirovirsen (HBV)

Phase 2b

Hepatitis B virus infection

Donidalorsen

Phase 2 OLE

HAE

Cimdelirsen (GHR)

Phase 2 (monotherapy)

Acromegaly

Anticipated Key 2022 Study Initiations

Program

Phase

Anticipated Indication

H1

H2

Sapablursen

2

Polycythemia vera

IONIS-MAPTRx (BIIB080)

2

Alzheimer’s disease

ION904 (AGT)

2

Uncontrolled hypertension

ION717 (PRNP)

1/2

Prion disease

Anticipated Key 2022 Technology Advancements

Program

Anticipated Advancement

H1

H2

SMA

Advance follow-on program

Muscle LICA

Advance into preclinical development (IND-supporting)

MsPA Backbone

Advance into preclinical development (IND-supporting)

✓ = achieved • = planned

All non-GAAP amounts referred to in this press release exclude non-cash compensation
expense related to equity awards. In 2021 all non-GAAP amounts also excluded expenses
related to the Akcea Merger and restructured commercial operations and the related tax
effects. Please refer to the detailed reconciliation of non-GAAP and GAAP measures, which is
provided later in this press release.

The Company’s revenue in the first quarter of 2022 increased more than 25 percent compared to the same period last year. The increase was driven by significant partner payments across multiple partnered programs, including $20 million from AstraZeneca for its share of the global Phase 3 program costs for eplontersen. Since Ionis is conducting the ongoing Phase 3 program for eplontersen, Ionis recognizes revenue for the reimbursements it receives from AstraZeneca for development expenses in the same period Ionis recognizes the related development expenses. Refer to the detailed table of costs and reimbursements for the eplontersen collaboration provided later in this release. The Company also earned $40 million from Biogen for advancing several neurology disease programs.

The Company successfully completed the transition of its TEGSEDI and WAYLIVRA operations in the EU and North America to Sobi in the first and second quarters of 2021, respectively. The decrease in TEGSEDI and WAYLIVRA revenue in the first quarter of 2022 compared to the same period last year was due to the shift from product sales to distribution fees based on net sales generated by Sobi. As part of the transition, Ionis restructured its commercial operations in 2021 resulting in substantial cost savings.

Operating Expenses

Ionis is advancing a large late-stage pipeline and as a result, its non-GAAP operating expenses increased in the first quarter of 2022 compared to the same period in 2021. Higher R&D expenses were driven by the expanded number of Phase 3 studies the Company is conducting, which doubled over the course of 2021 from three to six studies. Lower SG&A expenses were largely due to the substantial savings Ionis achieved from integrating Akcea and restructuring its commercial operations. These savings were offset in part by the investments Ionis made in advancing its go-to-market activities for its near-term commercial opportunities.

Net Loss

Ionis’ net loss in the first quarter of 2022 decreased compared to the same period in 2021 primarily related to the changes in revenue and operating expenses, as discussed above.

Balance Sheet

As of March 31, 2022 and December 31, 2021, Ionis had cash, cash equivalents and short-term investments of $2.1 billion. Ionis’ debt obligations and working capital did not change significantly from December 31, 2021 to March 31, 2022.

Webcast

Ionis will conduct a webcast today at 11:30 a.m. Eastern time to discuss this announcement and related activities. Interested parties may access the webcast here. A webcast replay will be available for a limited time at the same address.

DURECT Corporation Reports First Quarter 2022 Financial Results and Update of Programs

On May 4, 2022 DURECT Corporation (Nasdaq: DRRX) reported financial results for the three months ended March 31, 2022 and provided a corporate update (Press release, DURECT, MAY 4, 2022, View Source [SID1234613523]).

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"Progress continues in the larsucosterol (DUR-928) AHFIRM trial, with more patients dosed in the first quarter of 2022 than in any prior quarter, reflecting the opening of additional clinical trial sites and our ongoing efforts to work with existing sites to recruit more patients with severe alcohol-associated hepatitis (AH) that meet our enrollment criteria," stated James E. Brown, D.V.M., President and CEO of DURECT.

First Quarter and Recent Business Highlights:

Continued progress in AHFIRM enrollment – DURECT has now dosed the first patients in Australia, France and Belgium, with 57 AHFIRM study sites now open at leading hospitals in the U.S., Australia, E.U. and U.K., a net increase of 6 sites in the two months since our last earnings call. At the pace of enrollment achieved in the first quarter of 2022, we would complete dosing the last patient in the AHFIRM trial in mid-2023; we expect the pace of enrollment should improve through our clinical site expansion, clinical trial engagement activities and the potential lessening of the impact of COVID on the hospitals participating in AHFIRM.
Engaging thought leaders and increasing awareness of AH – DURECT’s medical affairs team has been substantially increasing our AH market outreach and education efforts to amplify larsucosterol awareness and facilitate AHFIRM enrollment efforts. We have recently hosted the first of multiple regional AHFIRM study update meetings with our investigators and study site coordinators, sponsored and exhibited at three liver-focused congresses in person, and retained a medical communications agency to broaden awareness of AH, the AHFIRM trial and larsucosterol.
Approaching U.S. launch of POSIMIR by our licensee – DURECT signed an exclusive U.S. licensing agreement for POSIMIR with Innocoll Pharmaceuticals in December 2021. Under the agreement, DURECT will earn low to mid double-digit royalties from net sales of POSIMIR and is eligible to receive up to $136 million in upfront and milestone payments, including the $4 million upfront license fee received in January 2022, and a $2 million milestone payment upon the first commercial sale of POSIMIR, which is anticipated in Q2 2022.
Financial highlights for Q1 2022:

Total revenues were $1.9 million and net loss was $10.8 million for the three months ended March 31, 2022 compared to total revenues of $2.2 million and net loss of $10.1 million for the three months ended March 31, 2021.
At March 31, 2022, cash and investments were $64.4 million, compared to cash and investments of $70.0 million at December 31, 2021. Debt at March 31, 2022 was $20.8 million, compared to $20.6 million at December 31, 2021.
Earnings Conference Call
We will host a conference call today at 4:30 p.m. Eastern Time/1:30 p.m. Pacific Time to discuss first quarter 2022 results and provide a corporate update:

A live audio webcast of the presentation will be also available by accessing DURECT’s homepage at www.durect.com and clicking "Investors." If you are unable to participate during the live webcast, the call will be archived on DURECT’s website under "Event Calendar" in the "Investors" section.

About the AHFIRM Trial
Enrollment is ongoing in our Phase 2b randomized, double-blind, placebo-controlled, international, multi-center study in subjects with severe acute alcohol-associated hepatitis (AH) to evaluate saFety and effIcacy of laRsucosterol (DUR-928) treatMent (AHFIRM). The study is comprised of three arms targeting enrollment of 300 total patients, with approximately 100 patients in each arm: (1) Placebo plus standard of care (SOC) which may include the use of methylprednisolone, a corticosteroid, at the discretion of the treating physician; (2) larsucosterol (30 mg); and (3) larsucosterol (90 mg). All patients in the trial receive supportive care. The primary outcome measure is 90-Day survival rate for patients treated with larsucosterol compared to those treated with placebo plus SOC. The Company is targeting more than 60 clinical trial sites across the U.S., EU, U.K., and Australia. Reflecting the life-threatening nature of AH and the lack of therapeutic options, the U.S. Food and Drug Administration (FDA) has granted larsucosterol Fast Track Designation for the treatment of AH. We believe demonstration of a robust survival benefit in the AHFIRM trial would support an NDA filing. For more information, refer to ClinicalTrials.gov Identifier: NCT04563026.

About Alcohol-associated Hepatitis (AH)
AH is a life-threatening acute alcohol-associated liver disease (ALD) often caused by chronic heavy alcohol use and a recent period of increased alcohol consumption (i.e., a binge). It is characterized by severe inflammation and destruction of liver tissue (i.e., necrosis), potentially leading to life-threatening complications including liver failure, acute renal injury and multi-organ failure. There are no FDA approved therapies for AH and an analysis of 77 studies published between 1971 and 2016, which included data from a total of 8,184 patients, showed the overall mortality from AH was 26% at 28 days, 29% at 90 days and 44% at 180 days. A subsequent global study published in December 2021, which included 85 tertiary centers in 11 countries across 3 continents, prospectively enrolled 2,581 AH patients with a median MELD score of 23.5, reported mortality at 28 and 90 days of 20% and 31% respectively. Stopping alcohol consumption is not sufficient for recovery in many moderate and severe patients and the use of treatments to reduce liver inflammation, such as corticosteroids, are limited by contraindications and have been shown to provide no survival benefit at 90 days or 1 year. While liver transplantation is becoming more common for alcoholic liver disease patients, including AH patients, the procedure involves a long waiting period, a burdensome selection process, and costs more than $875,000 on average.

About Larsucosterol (DUR-928)
Larsucosterol is an endogenous sulfated oxysterol and an epigenetic regulator. Epigenetic regulators are compounds that regulate patterns of gene expression without modifying the DNA sequence. DNA hypermethylation, an example of epigenetic dysregulation, results in transcriptomic reprogramming and cellular dysfunction, and has been found to be associated with many acute (e.g., AH) or chronic diseases (e.g., NASH). As an inhibitor of DNA methyltransferases (DNMT1, DNMT3a and 3b), larsucosterol inhibits DNA methylation, which subsequently regulates expression of genes that are involved in cell signaling pathways associated with stress responses, cell death and survival, and lipid biosynthesis. This may ultimately lead to improved cell survival, reduced inflammation, and decreased lipotoxicity. As an epigenetic regulator, the proposed mechanism of action provides further scientific rationale for developing larsucosterol for the treatment of acute organ injury and certain chronic diseases.