On February 27, 2019 Madrigal Pharmaceuticals, Inc. (NASDAQ:MDGL) reported its fourth quarter and full year 2018 financial results and highlights (Press release, Synta Pharmaceuticals, FEB 27, 2019, View Source [SID1234533732]):

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"Madrigal made significant progress in 2018 in advancing the development of MGL-3196. We successfully completed Phase 2 studies in both NASH and dyslipidemia and expanded the Madrigal team to meet the demands of our clinical programs," stated Paul Friedman, M.D., Chief Executive Officer of Madrigal. "In June, we also raised approximately $312 million of net proceeds from a public offering of our common stock, and we believe we have significant financial resources to fund our currently planned Phase 3 programs."

Becky Taub, M.D., CMO and Executive VP, Research & Development of Madrigal added, "We had a positive end of phase 2 meeting with FDA for our NASH program, and we expect to initiate our Phase 3 clinical trial before the end of the first quarter of 2019. We continue to believe MGL-3196 has the potential to resolve NASH while decreasing cardiovascular risk, through reduction of levels of multiple atherogenic lipids as well as reduction of fat in the liver. Based on this potential cardiovascular risk reducing profile, we also intend to move ahead with our Phase 3 dyslipidemia clinical program later this year."

Financial Results for the Three Months and Twelve Months Ended December 31, 2018

As of December 31, 2018, Madrigal had cash, cash equivalents and marketable securities of $483.7 million, compared to $191.5 million at December 31, 2017. The increase in cash and marketable securities resulted primarily from the net proceeds of $311.8 million from Madrigal’s public offering of common stock in June 2018, partially offset by cash used in operations of $25.5 million.

Operating expenses were $14.5 million and $40.7 million, respectively, for the three month and twelve month periods ended December 31, 2018, compared to $8.9 million and $32.1 million in the comparable prior year periods.

Research and development expenses for the three month and twelve month periods ended December 31, 2018 were $8.9 million and $25.4 million, respectively, compared to $6.5 million and $24.4 million in the comparable prior year periods. The increases are primarily attributable to increases in non-cash stock compensation, personnel and

consulting costs, the effects of which were partially offset by lower clinical costs due to completion of treatment in our Phase 2 clinical studies in 2018.

General and administrative expenses for the three month and twelve month periods ended December 31, 2018 were $5.6 million and $15.3 million, respectively, compared to $2.4 million and $7.7 million in the comparable prior year periods. The increases are due primarily to higher non-cash stock compensation expense from stock option awards.

Interest income for the three month and twelve month periods ended December 31, 2018 was $3.0 million and $7.7 million, respectively, as compared to $216 thousand and $558 thousand in the comparable prior year periods. The change in interest income was due primarily to a higher average principal balance in our investment account in 2018, and increased interest rates.

Clinical Program Summaries for MGL-3196

NASH

Non-alcoholic Steatohepatitis (NASH) is a common liver disease in the United States and worldwide, unrelated to alcohol use, that is characterized by a build-up of fat in the liver, inflammation, damage (ballooning) of hepatocytes and increasing fibrosis. Although people with NASH may feel well and often do not know they have the disease, NASH can lead to permanent damage, including cirrhosis and impaired liver function in a high percentage of patients.

In October 2016, the first patient was treated in the ongoing Phase 2 trial of MGL-3196 for the treatment of NASH. The randomized, double-blind, placebo-controlled, multi-center Phase 2 study enrolled 125 patients 18 years of age and older with liver biopsy-confirmed NASH and included approximately 25 clinical sites in the United States. Patients were randomized to receive either MGL-3196 or placebo in a 2:1 ratio.

The primary endpoint of the study was the reduction of liver fat at 12 weeks compared with baseline (relative change), assessed by MRI-PDFF. Key secondary endpoints at 36 weeks included: reduction in liver fat compared with baseline (relative change), also assessed by MRI-PDFF; a two-point reduction in NAS (NALFD activity score) on biopsy; resolution of NASH on biopsy; and, safety and tolerability based on adverse events and changes in laboratory values.

The primary endpoint of the study at 12 weeks was achieved. Liver fat was reduced by 36.3% in all MGL-3196 treated patients (78) and 42.0% in a pre-specified group of high exposure MGL-3196 treated patients (44/78), as compared with 9.6% median reduction in liver fat in 38 placebo treated patients. These results were statistically significant (p<0.0001) for both MGL-3196 treatment groups. Further, 75% of the high-exposure MGL-3196 treated patients showed liver fat reductions of >30%.

At 36 weeks, MGL-3196 achieved multiple key secondary endpoints including a sustained highly significant (p<0.001) reduction in liver fat compared to placebo as measured by MRI-PDFF; mean relative fat reduction for MGL-3196 was 37% versus 8.9% for placebo. MGL-3196 was associated with a greater percentage of subjects with a 2-point improvement in NAS (56% of 73 patients vs 32% of 34 placebo subjects, p=0.02). NASH resolution (NR) was seen in 27% of MGL-3196 compared with 6% of placebo subjects, p=0.02. MGL-3196 patients with > 30% fat reduction on Week 12 MRI-PDFF demonstrated a higher percentage of 2-point improvement in NAS (70%, p=0.001) and NR (39%, p=0.001) compared with placebo, demonstrating a strong relationship between early reduction in liver fat as demonstrated by week 12 MRI-PDFF and NASH improvement on liver biopsy at Week 36. In patients with NASH Resolution, 35% of the MGL-3196 treated patients and no placebo patients had more advanced NASH (baseline NAS >5).

At Week 36, MGL-3196 treated patients showed sustained reduction of fibrosis biomarkers. In MGL-3196 patients with NASH resolution, fibrosis also resolved in 50% of patients and was decreased statistically significantly relative to all placebo patients.

There were statistically significant reductions in liver enzymes in MGL-3196 treated patients compared to placebo treated patients; reductions of greater magnitude were achieved with longer duration of MGL-3196 treatment. Statistically significantly more MGL-3196 treated patients than placebo treated patients had normalization of ALT (alanine transaminase).

Similar to week 12, at week 36 there were sustained, statistically significant reductions in low-density lipoprotein cholesterol (LDL-C), triglycerides, ApoB and lipoprotein(a).

MGL-3196 was well tolerated in this trial with mostly mild and a few moderate AEs which were balanced between drug treated and placebo patients. There was an increase in incidence of mild transient diarrhea in MGL-3196-treated, often a single episode, at the start of treatment. Diarrhea incidence was not increased later in the study.

Based on liver enzyme inclusion criteria, some patients are receiving extended treatment beyond 36 weeks for up to 36 additional weeks. All patients in this extension study will receive MGL-3196 and only non-invasive assessments will be made, including serial MRI-PDFF, safety labs, and circulating biomarkers.

Additional information about the study [NCT02912260] can be obtained at www.ClinicalTrials.gov.

Dyslipidemia

Patients with NASH, and its more prevalent precursor, Non-Alcoholic Fatty Liver Disease (NAFLD), are at heightened cardiovascular risk. In fact, patients suffering from these conditions die more frequently from cardiovascular events than from their liver

disease. Multiple factors may contribute to this risk, including elevated levels of LDL-C and excess liver fat. Patients with NASH and NAFLD, however, may not undergo a biopsy to confirm a NASH diagnosis until they reach the more advanced stages of fibrosis (F2 — F4). A significant segment of this large group of patients may also suffer from diabetes and metabolic syndrome, and have lipid levels that are above target despite treatment with established therapies. These patients may benefit from therapy to lower their lipid levels, including excess liver fat.

We believe Madrigal’s studies to date in patients with NASH and patients with heterozygous familial hypercholesterolemia (HeFH), have demonstrated the pleiotropic activity of MGL-3196 and the potential of the drug to reduce an array of atherogenic lipids, including liver fat, LDL-C, ApoB, triglycerides, ApoCIII, and Lp(a), as well as hs-CRP. As a result, Madrigal intends to focus its development of MGL-3196 for the treatment of patients across the entire NASH and NAFLD spectrum.

HeFH
Heterozygous familial hypercholesterolemia (HeFH), and a much rarer form called homozygous familial hypercholesterolemia (HoFH), are severe genetic dyslipidemias typically caused by inactivating mutations in the LDL receptor. Both forms of FH lead to early onset cardiovascular disease. HeFH, the most common dominantly inherited disease, is present in up to 1 in 200 people; the disease is found in higher frequencies in certain more genetically homogenous populations. Treatments exist for both HeFH and HoFH but many patients (as many as 40 percent of HeFH patients) are not able to reach their cholesterol (LDL-C) reduction goals on these therapies, reflecting the lifetime burden of cholesterol buildup in their bodies. Based on evidence of impressive LDL cholesterol lowering in Phase 1, and data suggesting that MGL-3196 has a mechanism of action that is different from and complementary to statins, Madrigal initiated a Phase 2 proof-of-concept trial in HeFH in February 2017 and enrolled 116 patients.

In this Phase 2 HeFH trial, patients who were not at their LDL-C goal were randomized in a 2:1 ratio to receive either MGL-3196 or placebo, in addition to their current cholesterol lowering regimen, which included approximately 75% taking high intensity statins (20/40 mg rosuvastatin or 80 mg atorvastatin), and about 2/3 of patients also taking ezetimibe. MGL-3196 treated patients (placebo corrected) achieved highly significant (p< 0.0001) LDL-C lowering of 18.8%, and 21% LDL-C lowering in those on an optimal dose of MGL-3196. LDL-C lowering was 28.5% in MGL-3196 treated compared to placebo in a prespecified group of patients who did not tolerate high intensity statin doses. Highly significant reductions (p<0.0001) relative to placebo were also observed with ApoB, triglycerides (TG) (25-31%), apolipoprotein CIII (Apo CIII) and Lp(a) (25-40%) in all MGL-3196 treated patients and prespecified subgroups, irrespective of statin treatment.

MGL-3196 was well-tolerated with primarily mild and some moderate AEs, the numbers of which were balanced between placebo and drug-treatment groups.

About MGL-3196

Among its many functions in the human body, thyroid hormone, through activation of its beta receptor, plays a central role in controlling lipid metabolism, impacting a range of health parameters from levels of serum cholesterol and triglycerides to the pathological buildup of fat in the liver. Attempts to exploit this pathway for therapeutic purposes in cardio-metabolic and liver diseases have been hampered by the lack of selectivity of older compounds for the thyroid hormone receptor (THR)-β, chemically-related toxicities and undesirable distribution in the body.

Madrigal recognized that greater selectivity for thyroid hormone receptor (THR)-β and liver targeting might overcome these challenges and deliver the full therapeutic potential of THR-β agonism. Madrigal believes that MGL-3196 is the first orally administered, small-molecule, liver- directed, truly β-selective THR agonist. MGL- 3196 has now demonstrated in two Phase 2 double-blind, placebo-controlled trials in NASH and HeFH the potential for a broad array of therapeutically beneficial effects, improving components of both metabolic syndrome, such as insulin resistance and dyslipidemia, and fatty liver disease, including lipotoxicity and inflammation. Based on evidence of these pleiotropic actions, coupled with an excellent safety profile, Madrigal plans to initiate a Phase 3 clinical program in NASH, and a Phase 3 clinical program is dyslipidemia

On February 27, 2019 Can-Fite BioPharma Ltd. (NYSE American: CANF) (TASE:CFBI), a biotechnology company advancing a pipeline of proprietary small molecule drugs that address cancer, liver and inflammatory diseases, reported the Company’s VP of Business Development, Sari Fishman will participate in the Bio Asia International Conference in Tokyo, Japan on March 5th and 6th, 2019.

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The BIO Asia International Conference brings together the global biotechnology and pharmaceutical industry to explore licensing collaborations and investor engagement in the current Asia-Pacific business and policy environments.

Dr. Fishman is scheduled to conduct more than 20 one-on-one meetings with business development officers from leading pharmaceutical companies interested in learning more about Can-Fite’s advanced stage drug candidates.

Can-Fite’s current pharma partnerships in Asia include distribution and development agreements with Kwang Dong in Korea for Piclidenoson, Chong Kun Dang in Korea for Namodenoson, and CMS in China for Piclidenoson and Namodenoson. The Company sees substantial additional partnership opportunities in Asia.

On February 27, 2019 Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) reported financial results for the fourth quarter and full year 2018 and reviewed highlights of its successful year (Press release, Ionis Pharmaceuticals, FEB 27, 2019, View Source [SID1234533727]).

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"We begin 2019 in the strongest position in our 30-year history. Building on this foundation, we believe we are positioned for continued growth," said Stanley T. Crooke, M.D., Ph.D., chairman of the board and chief executive officer of Ionis. "In 2018, we launched TEGSEDI globally through our affiliate, Akcea, adding revenue from TEGSEDI sales to our substantial commercial revenue from SPINRAZA. We also achieved many important milestones in our pipeline, particularly among the medicines within our late-stage pipeline. This week, Novartis exercised its option to license AKCEA-APO(a)-LRx for which we earned $150 million. Novartis plans to initiate a Phase 3 cardiovascular outcomes study and initiation activities are already underway. We and Akcea are finalizing Phase 3 study designs for the AKCEA-TTR-LRx pivotal program that we plan to initiate in the second half of this year. In addition, our late-stage neurological disease programs recently achieved important milestones. Roche is now enrolling patients in the Phase 3 study of IONIS-HTTRx for Huntington’s disease and Biogen is planning to add an additional cohort to the ongoing study of IONIS-SOD1Rx for patients with SOD1-related ALS that has the potential to support marketing approval. We achieved these successes while growing revenues, investing in the commercialization of TEGSEDI, advancing our broad and diverse pipeline, and consistently leading our industry in innovation – demonstrating the success of our business model and robust technology platform."

2018 Financial Results and Highlights

Revenues increased by 17 percent compared to 2017

Total revenue was $600 million compared to $514 million in 2017.

Commercial revenue from SPINRAZA for 2018 was $238 million, more than double compared to 2017.

TEGSEDI sales were $2.2 million in the fourth quarter of 2018, with commercial sales commencing in the EU in October and in the U.S. in December.

Commercial revenue was over 40 percent of total revenue in 2018 compared to less than 25 percent in 2017, reflecting Ionis’ transition to a commercial-stage company.

Achieved third consecutive year of non-GAAP operating profitability

GAAP operating income was $11 million for the fourth quarter and an operating loss of $61 million for the full year 2018, compared to an operating loss of $6 million and operating income of $31 million for the same periods in 2017.

Non-GAAP operating income was $45 million for the fourth quarter and $70 million for the full year 2018, compared to operating income of $16 million and $117 million for the same periods in 2017

Operating expenses increased in 2018 primarily due to investment in the commercialization of TEGSEDI.

Strong financial results trigger the recognition of a significant tax benefit

In 2018, Ionis reported GAAP net income attributable to Ionis common stockholders of $274 million, primarily driven by a $291 million one-time non-cash income tax benefit Ionis recorded in 2018 related to its income tax assets.

Because of Ionis’ strong financial performance over the past few years and its outlook regarding the continued growth of its business, the Company believes it is more likely than not that it will be able to use the significant amount of income tax assets it has accumulated to offset future taxable income.

Substantial cash position of over $2 billion enables continued investment in commercial products and pipeline

2019 Financial Guidance

"Building upon our success in 2018, we expect to continue our momentum this year and beyond. We anticipate both commercial and R&D revenues to contribute to our overall earnings growth this year, potentially making 2019 our fourth consecutive year of non-GAAP operating profitability. And for the first time, due to our strong financial performance in recent years and strong confidence in our future, we are projecting to be profitable on the bottom line on a non-GAAP basis in 2019. We believe our ability to be profitable while investing in commercial activities, fully exploiting our pipeline and advancing our technology, clearly sets us apart from our peers," said Elizabeth L. Hougen, chief financial officer of Ionis.

All non-GAAP amounts referred to in this press release exclude non-cash compensation expense related to equity awards. Please refer to the reconciliation of non-GAAP and GAAP measures, which is provided later in this release. In prior financial results releases, Ionis referred to amounts that excluded non-cash compensation expense related to equity awards as "pro forma". Additionally, Ionis has labeled its prior period financial statements "as revised" to reflect the revenue recognition accounting standard the Company adopted on January 1, 2018.

Business Highlights

·
SPINRAZA – the worldwide standard-of-care for the treatment of all people with spinal muscular atrophy

o
In 2018, SPINRAZA sales nearly doubled to $1.7 billion compared to 2017, driven by growth in the U.S. and outside the U.S., as reported by Biogen.

o
As of the fourth quarter of 2018, more than 6,600 SMA patients from over 40 countries were on SPINRAZA, including commercial patients and patients in the expanded access program and clinical trials.

o
In the fourth quarter of 2018, the number of adult patients on therapy in the U.S. grew by over 20 percent compared to the third quarter, accounting for more than 50 percent of new patient starts in the U.S.

·
TEGSEDI (inotersen) – launch underway in multiple markets for the treatment of polyneuropathy of hereditary transthyretin amyloidosis (hATTR) in adult patients

o
TEGSEDI generated $2.2 million in sales from the U.S. and EU in its first quarter of launch.

o
PTC Therapeutics, Ionis and Akcea’s commercialization partner in Latin America, filed for marketing authorization for TEGSEDI in Brazil and was granted priority review.

Key Upcoming Events

·
Roche plans to present data from the OLE study of IONIS-HTTRx in patients with Huntington’s disease in 2019.
·
Biogen plans to present data from the completed portions of the Phase 1/2 study of IONIS-SOD1Rx in 2019.
·
Ongoing regulatory discussions on WAYLIVRA in the EU, and if approved, launch.
·
Ionis and its partners plan to report data from numerous Phase 2 studies including IONIS-FXIRx, IONIS-HBVRx and IONIS-GHR-LRx.

Revenue

Ionis’ revenue in the three months and year ended December 31, 2018 was $192 million and $600 million, respectively, compared to $168 million and $514 million for the same periods in 2017 and was comprised of the following (amounts in millions):

The increase in revenue in 2018 compared to 2017 was primarily due to increasing commercial revenue from SPINRAZA royalties, which more than doubled. Additionally, Ionis earned more than $2 million from TEGSEDI product sales in the fourth quarter of 2018.

Ionis’ R&D revenue demonstrates the Company’s ability to generate sustainable revenue from its numerous partnerships. R&D revenue from the amortization of upfront payments increased over $25 million in 2018 compared to 2017. The increase in amortization was primarily due to Ionis’ 2018 strategic neurology collaboration with Biogen. Also, in 2018, Ionis added amortization revenue from its new collaboration with Roche to develop IONIS-FB-LRx. Ionis’ R&D revenue from milestone payments, license fees and other services for 2018 continued to make a significant contribution to Ionis’ financial results.

Already in the first quarter of 2019, Ionis has earned $185 million. The Company earned $150 million from Novartis when it licensed AKCEA-APO(a)-LRx and $35 million from Roche when it enrolled the first patient in the Phase 3 study of IONIS-HTTRx in patients with Huntington’s disease.

Operating Expenses

Operating expenses for the three months and year ended December 31, 2018 on a GAAP basis were $181 million and $661 million, respectively, and on a non-GAAP basis were $147 million and $530 million, respectively. These amounts compare to GAAP operating expenses for the three months and year ended December 31, 2017 of $174 million and $483 million, respectively, and non-GAAP operating expenses of $152 million and $397 million, respectively. The full year increase in operating expenses in 2018 compared to 2017 was principally due to Ionis’ investments in the global launch of TEGSEDI. The Company’s SG&A expenses also increased due to an increase in fees the Company owed under its in-licensing agreements related to SPINRAZA, due to increased SPINRAZA product sales.

Income Tax Benefit

Ionis reported an income tax benefit of $292 million and $291 million for the three months and year ended December 31, 2018, respectively, compared to $7 million and $6 million for the same periods in 2017. Ionis’ tax benefit increased significantly in 2018 primarily due to a one-time non-cash tax benefit related to its deferred income tax assets. In the fourth quarter of 2018, the Company released a large portion of the valuation allowance associated with its deferred tax assets. Because of Ionis’ strong financial performance over the past few years and its outlook regarding the continued growth of its business, the Company determined that it is more likely than not that it will be able to utilize most of the deferred income tax assets it has accumulated to offset future taxable income.

Net Loss Attributable to Noncontrolling Interest in Akcea

At December 31, 2018, Ionis owned approximately 75 percent of Akcea. The shares of Akcea third parties own represent an interest in Akcea’s equity that Ionis does not control. However, because Ionis continues to maintain overall control of Akcea through its voting interest, Ionis reflects the assets, liabilities and results of operations of Akcea in Ionis’ consolidated financial statements. Ionis reflects the noncontrolling interest attributable to other owners of Akcea’s common stock in a separate line called "Net loss attributable to noncontrolling interest in Akcea" on Ionis’ statement of operations. Ionis’ net loss attributable to noncontrolling interest in Akcea for the three months and year ended December 31, 2018, was $17 million and $59 million, respectively. Ionis’ net loss attributable to noncontrolling interest in Akcea for the three months and year ended December 31, 2017, was $6 million and $11 million, respectively.

Net Income (Loss) Attributable to Ionis Common Stockholders

Ionis reported net income attributable to Ionis’ common stockholders of $320 million and $274 million for the three months and year ended December 31, 2018, respectively, compared to a net loss of $3 million and net income of $0.3 million for the same periods in 2017, all on a GAAP basis. On a non-GAAP basis, Ionis reported net income attributable to Ionis’ common stockholders of $351 million and $394 million for the three months and year ended December 31, 2018, respectively, compared to $18 million and $85 million for the same periods in 2017. The increase in 2018 net income attributable to Ionis’ common stockholders was primarily due to increases in revenue and the income tax benefit Ionis recognized in the fourth quarter of 2018.

For the three months ended December 31, 2018, basic and diluted net income per share were $2.32 and $2.21, respectively. For the year ended December 31, 2018, basic and diluted net income per share were $2.09 and $2.07, respectively. For the three months ended December 31, 2017, basic and diluted net loss per share were each $0.03. For the year ended December 31, 2017, basic and diluted net income per share were each $0.15. All amounts are on a GAAP basis.

Balance Sheet

As of December 31, 2018, Ionis had cash, cash equivalents and short-term investments of $2.1 billion compared to $1.0 billion at December 31, 2017. The increase in Ionis’ cash, cash equivalents and short-term investments was primarily due to the $1 billion Ionis received from Biogen for the 2018 strategic neurology collaboration.

Webcast and Conference Call

Today, at 11:30 a.m. Eastern Time, Ionis will conduct a live webcast conference call to discuss this earnings release and related activities. Interested parties may listen to the call by dialing 877-443-5662 or access the webcast at www.ionispharma.com. A webcast replay will be available for a limited time.

On February 27, 2019 Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, reported financial results for the fourth quarter and year ended December 31, 2018 and provided a business update (Press release, Adaptimmune, FEB 27, 2019, View Source [SID1234533726]).

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"2018 was a year of strong delivery across the portfolio with record numbers of patients treated in our clinical trials. We moved through the dose escalation portion of our studies with ADP-A2M4 and ADP-A2M10 and we are now treating patients in the expansion phases for both programs. Our third program, ADP-A2AFP, moved to the second dose cohort at target doses of 1 billion cells. We are very pleased to have observed an acceptable safety profile, thus far, with all three programs, showing no evidence of off-target toxicity or alloreactivity," said James Noble, Chief Executive Officer. "We are now able to devote our resources to these programs following the successful transition of NY-ESO to GSK."

"We made equally impressive progress in manufacturing with our in-house facility going from our first ever dose, at the beginning of 2018, to being able to produce target doses for up to 10 patients per month. In the UK, we started up our vector manufacturing that should begin to produce vector later this year. 2019 promises to be a significant year, with data emerging across our portfolio from May onwards. We look forward to reporting clinical data throughout the year," added James Noble.

Clinical momentum

Initial safety testing is complete in the triple tumor and non-small cell lung cancer (NSCLC) studies with ADP-A2M10, as well as the basket study with ADP-A2M4. All three studies are enrolling and treating patients with up to 10 billion cells in the expansion phases with no pre-determined stagger between dosing required.

In 2018, the Safety Review Committee (SRC) endorsed dose escalation through Cohorts 1, 2, and 3 of these studies, after reviewing safety data from 16 patients treated in the ADP-A2M10 studies and nine patients in the ADP-A2M4 study.

In the hepatocellular carcinoma study with ADP-A2AFP, the SRC endorsed escalation to safety Cohort 2 to treat patients with a target dose of 1 billion cells.

To date, across all four studies, most adverse events have been consistent with those typically experienced by cancer patients undergoing cytotoxic chemotherapy or other cancer immunotherapies with no evidence of alloreactivity or toxicity related to off-target binding.

Building an integrated company

Since the opening of the Navy Yard facility in January 2018, Adaptimmune can now manufacture cells for up to 10 patients per month, and this is scalable to 100 patients per month without significant capital expenditure. Further, an additional 10 patients per month can be treated with cells produced at a third-party vendor HCATs. Both the Navy Yard and HCATs facilities are now able to routinely produce cells to meet target doses across a broad range of solid tumors. This capacity will allow Adaptimmune to service its existing and planned clinical trials.

With respect to vector, Adaptimmune is well supplied as its own vector manufacturing has completed its first engineering run with first production anticipated in 2019, as well as production in place at a third-party vendor. The vendor has already produced vector for ADP-A2M10, ADP-A2M4, ADP-A2AFP, and next generation SPEAR T-cells.

In light of the Company’s increased clinical focus, Rafael Amado assumed the new role of President of R&D last year to bring the clinical and research functions under a single leadership, facilitating alignment and integration of all parts of the R&D structure.

The Company is working with more than 20 active clinical trial sites at leading cancer centers in the US, Canada, and the EU. In Europe, the infrastructure has been tested and has delivered the first doses to patients with additional patients being enrolled in the UK and Spain. Adaptimmune has also reached agreement on an expanded collaboration with MD Anderson Cancer Center (Houston, TX) to further enhance the Company’s translational research capabilities.

While progressing studies with ADP-A2M10, ADP-A2M4, and ADP-A2AFP as well as planning for the next stage of clinical development, including potential registration trials, Adaptimmune continues to progress developing next generation SPEAR T-cells, new targets, other HLAs, and an off-the-shelf product.

Finally, Adaptimmune is funded through to late 2020, based on management’s current estimates, with Total Liquidity(1) of $205 million (including cash and cash equivalents of $68 million) at year-end 2018.

2018 Highlights

Clinical progress with wholly-owned programs:

·ADP-A2M10 (MAGE-A10):

·January 2018: The SRC endorsed escalation to Cohort 2 (1 billion target dose) in the ADP-A2M10 triple tumor and lung studies based on favorable safety data

·ASCO: Poster presented at ASCO (Free ASCO Whitepaper) with initial safety data

·July: SRC endorsed dose escalation to Cohort 3 in the NSCLC and triple tumor studies, and treating patients at target dose of 5 billion cells commenced

·ESMO: Presentation of Cohorts 1 and 2 safety data showing dose proportionate persistence and expansion

·Q4: Escalation to expansion phase allowing for doses up to 10 billion cells with no pre-determined stagger between patients for both studies

·ADP-A2M4 (MAGE-A4) — Basket study:

·ASCO: The SRC endorsed escalation to Cohort 2 based on favorable safety data in Cohort1. Added synovial sarcoma and myxoid/round cell liposarcoma (MRCLS) indications for a total of nine solid tumors in this study

·August: Dose escalation to Cohort 3

(1) Total liquidity is a non-GAAP financial measure, which is explained and reconciled to the most directly comparable financial measures prepared in accordance with GAAP below.

· ESMO (Free ESMO Whitepaper): Presentation of Cohorts 1 and 2 safety data showing dose appropriate persistence and expansion, and early, but transient, evidence of antitumor activity in one ovarian cancer patient

· Q4: Escalation to expansion phase allowing for doses up to 10 billion cells with no pre-determined stagger between patients

·ADP-A2AFP (AFP) – Hepatocellular carcinoma:

· SRC endorsed escalation to Cohort 2 with target doses of 1 billion cells

· Clinical learnings

· AACR (Free AACR Whitepaper) 2018: Presented two posters with ADP-A2M10 and ADP-A2M4 preclinical data

· Q2: Published study in Cancer Discovery indicating that NY-ESO SPEAR T-cells are long-lived, self-renewing, and capable of persistent anti-tumor effects

· SITC (Free SITC Whitepaper): Updated data supporting further understanding of systemic and local immunity following NY-ESO treatment in synovial sarcoma, including the positive impact of a more intense pre-conditioning regimen with respect to SPEAR T-cell expansion and persistence; adjusted to a more intense pre-conditioning regimen in current trials as a result

· Q4: Published paper in Hepatology "Tuning T-cell receptor affinity to optimize clinical risk-benefit when targeting α-fetoprotein (AFP) positive liver cancer," which details the development of the SPEAR T-cells targeting AFP

Preclinical:

· Good progress with off-the-shelf product and presented progress to date at ASGCT (Free ASGCT Whitepaper) 2018

· Developing multiple next generation approaches — first candidate ready for IND submission in 2H 2019

·Investigated new targets and additional HLAs to be brought to the clinic beyond 2019

Well-developed preclinical package including proprietary methods for predicting binding of a TCR to an off-target peptide utilizing alanine scanning processes. A licensing program is available to third parties wishing to use this patented method.

Manufacturing:

· Routinely producing cell product at target doses across a broad range of solid tumor indications

· Navy Yard facility now capable of manufacturing cell product for up to 10 patients per month (scalable to 100 patients per year) with capacity for an additional 10 patients per month at a third-party supplier HCATs

· Implemented rapid sterility testing to decrease vein-to-vein time

· Routinely producing more than 5 billion cells to meet target doses

· Agreement with third-party vector manufacturer for commercial supply — batches manufactured for ADP-A2M10, ADP-A2M4, ADP-A2AFP, and next generation SPEAR T-cells

· In-house suspension vector manufacturing capacity with an engineering run completed and first production expected in 2019

NY-ESO Program (now transitioned to GSK):

· Myxoid/round cell liposarcoma: Initial responses observed in a second solid tumor indication with data presented at ASCO (Free ASCO Whitepaper) 2018 and updated at SITC (Free SITC Whitepaper) 2018

· Agreement with GSK:

· Completed transition of the NY-ESO SPEAR T-cell development program in August 2018

· GSK assumed full responsibility for future research, development, and potential commercialization of NY-ESO now called GSK3377794 (GSK ‘794)

· Adaptimmune received ~ $27.5 million (~£21.2 million) in 2018 from GSK for completion of the transition

Other corporate news:

·Completed Registered Direct Offering, raising total net proceeds of ~$100 million in September 2018

· Appointed John Furey as an independent Non-Executive Director, effective July 5, 2018, succeeding Dr. Peter Thompson

Financial Results for the fourth quarter and year ended December 31, 2018

·Cash / liquidity position: As of December 31, 2018, Adaptimmune had cash and cash equivalents of $68.4 million and Total Liquidity(1) of $205.1 million.

·Revenue: Revenue represents the upfront and milestone payments, which are recognized as delivered services to GSK. Revenue for the fourth quarter and year ended December 31, 2018 were $1.5 million and $59.5 million compared to $4.3 million and $37.8 million for the same periods of 2017. Revenue in the year ended December 31, 2018 includes $39.1 million of revenue for the license to NY-ESO, which commenced in September 2018.

·Research and development ("R&D") expenses: R&D expenses for the fourth quarter and year ended December 31, 2018 were $22.8 million and $98.3 million, compared to $25.1 million and $87.4 million for the same periods of 2017. The increase was primarily due to increased costs associated with clinical trials; costs of developing manufacturing capability in the Company’s U.S. facility and increased personnel expenses.

· General and administrative ("G&A") expenses: G&A expenses for the fourth quarter and year ended December 31, 2018 were $10.8 million and $43.6 million, compared $8.8 million and $31.1 million for the same periods of 2017. The increase was primarily due to increased personnel costs consistent with our planned growth an increase in costs associated with supporting and maintaining our IT infrastructure.

·Net loss: Net loss attributable to holders of the Company’s ordinary shares for the fourth quarter and year ended December 31, 2018 were $36.2 million and $95.5 million ($(0.16) per ordinary share) compared to $27.3 million and $70.1 million ($(0.13) per ordinary share) in the same periods of 2017.

Financial Guidance

The Company believes that its existing cash and cash equivalents, short-term deposits and marketable securities, Total Liquidity, will fund the Company’s current operating plan through to late 2020.

Conference Call Information

The Company will host a live teleconference and webcast to provide additional details at 8:00 a.m. EST (1:00 p.m. GMT) today, February 27, 2019. The live webcast of the conference call will be available via the events page of Adaptimmune’s corporate website at www.adaptimmune.com. An archive will be available after the call at the same address. To participate in the live conference call, if preferred, please dial (833) 652-5917 (U.S. or Canada) or +1 (430) 775-1624 (International). After placing the call, please ask to be joined into the Adaptimmune conference call and provide the confirmation code (9455267).

On February 27, 2019 Intellia Therapeutics, Inc. (NASDAQ:NTLA), a leading genome editing company focused on developing curative therapeutics using CRISPR/Cas9 technology in both in vivo and ex vivo applications, reported operational highlights and financial results for the fourth quarter and year ended December 31, 2018 (Press release, Intellia Therapeutics, FEB 27, 2019, View Source [SID1234533717]). In addition, Intellia highlighted select corporate milestones for 2019 and upcoming events for the first quarter of 2019.

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"We are delivering on our full-spectrum strategy, and we expect to have two candidates in development in 2019. Our in vivo transthyretin amyloidosis program is on track for IND filing in 2020, and by the end of this year we anticipate having our first engineered cell therapy development candidate targeting acute myeloid leukemia," said Intellia President and Chief Executive Officer John Leonard, M.D. "We have shown that a single lipid nanoparticle administration can produce very substantial transthyretin protein reduction in non-human primates, reaching levels that we believe hold great therapeutic promise for patients. We also look forward to sharing additional data on our acute myeloid leukemia program this year. We believe our TCR-based, CRISPR-engineered cell therapy will provide a much-needed option for patients."

Recent Operational Highlights

ATTR Program: During the fourth quarter, Intellia completed confirmatory non-human primate (NHP) studies, previewed in October, using its lead candidate for the treatment of transthyretin amyloidosis (ATTR). Fifty-one days post infusion, these NHP studies verified a favorable tolerability profile across various dose levels, and a near-complete (average of >95 percent) reduction in circulating transthyretin (TTR) protein in the liver. The improvements in TTR protein reduction were the result of certain modifications made to the lipid nanoparticle (LNP) cargo components of the therapy, and these modifications have been incorporated into the ongoing, dose-range finding studies and scale-up activities. These modifications will also have application in subsequent programs. The ATTR program is being co-developed with Regeneron Pharmaceuticals, Inc. (Regeneron) with Intellia being the lead party. Intellia confirmed that it is on track for submitting an Investigational New Drug (IND) application in 2020 for ATTR.
In Vivo Insertion: In October, Intellia demonstrated in vivo CRISPR-mediated, targeted transgene insertion in mouse liver. Data shared at the Annual Congress of the European Society of Gene and Cell Therapy highlighted the use of Intellia’s bi-directional DNA template, delivered in a proprietary hybrid LNP/adeno-associated viral (AAV) template delivery system. Insertion of the human F9 gene, the gene encoding the protein deficient in hemophilia B, yielded Factor IX protein levels in mice at or above therapeutic targets in patients. This work was done in collaboration with Regeneron. Additionally, the Company demonstrated the versatility of the hybrid LNP/AAV approach by successfully inserting a functional human SERPINA1 gene (encoding alpha-1 antitrypsin) into the same locus. These experiments in mice yielded human protein expression levels consistent with those of normal individuals without alpha-1 antitrypsin deficiency.
Engineered Cell Therapies: As part of the broad engineered cell therapy platform that the Company is developing, Intellia and its partner, Ospedale San Raffaele, isolated novel active T cell receptors (TCRs) recognizing an epitope of the Wilms’ Tumor 1 (WT1) protein. This protein is overexpressed in many blood cancers, as well as in solid tumors. T cells modified with these TCRs successfully killed acute myeloid leukemia (AML) blasts in an in vitro model. This work will be the foundation for the Company’s first wholly owned ex vivo development candidate for the treatment of AML.
Novartis: In December, Intellia announced an expansion of the existing cell therapy collaboration with Novartis Institutes for Biomedical Research, Inc. (Novartis) to include ocular stem cells. The Company received a $10 million payment from Novartis in relation to the inclusion of this cell type. Regarding its proprietary LNP delivery system and improvements, Intellia also obtained expanded access to Novartis’ LNP library, including the rights to use these lipids for in vivo or ex vivo applications in any genome editing technology.
Board of Directors: In January of 2019, Intellia appointed Fred Cohen, M.D., D.Phil, F.A.C.P., to its board of directors, adding both biotechnology drug development experience and extensive medical expertise to the current knowledge base of the Company’s board.
Upcoming Milestones

The Company has set forth the following for 2019 pipeline progression:

ATTR: Complete dose-range finding studies, initiate IND-enabling toxicology studies and commence manufacturing of lipid and CRISPR/Cas9 cargo
Engineered Cell Therapy: Nominate first engineered cell therapy development candidate for acute myeloid leukemia by the end of 2019
Present additional in vivo NHP insertion data and ATTR formulation improvement data at upcoming scientific conferences
Upcoming Events

The Company will participate in the following investor events:

Leerink Healthcare Conference, February 28, New York City
Barclays Global Healthcare Conference, March 12, Miami
Fourth Quarter and Full Year 2018 Financial Results

Cash Position: Cash, cash equivalents and marketable securities were $314.1 million as of December 31, 2018, compared to $340.7 million as of December 31, 2017. The decrease was driven by cash used to fund operations of approximately $96 million, which was offset in part by $28.5 million of net equity proceeds raised from the Company’s "At the Market" (ATM) agreement, $11.7 million in proceeds from employee-based stock plans, $10.4 million of ATTR cost reimbursements made by Regeneron, and $19.0 million of funding received under the Novartis collaboration. The Novartis funding received included a $10.0 million upfront payment related to the expansion of the existing collaboration in the fourth quarter of 2018.
Collaboration Revenue: Collaboration revenue increased by $1.2 million to $7.9 million during the fourth quarter of 2018, compared to $6.7 million during the fourth quarter of 2017. The increase in collaboration revenue in 2018 was primarily driven by amounts recognized from the expansion of the existing collaboration with Novartis, as well as by amounts recognized under the Company’s ATTR Co/Co agreement with Regeneron. As previously disclosed, Regeneron is obligated to fund approximately 50 percent of the development costs for the ATTR program.
R&D Expenses: Research and development expenses decreased by $1.3 million to $19.9 million during the fourth quarter of 2018, compared to $21.2 million during the fourth quarter of 2017. This decrease was driven primarily by lower consumable costs, as well as the timing of general R&D expenses.
G&A Expenses: General and administrative expenses decreased by $1.5 million to $8.7 million during the fourth quarter of 2018, compared to $10.2 million during the fourth quarter of 2017. This decrease was driven primarily by a decrease in stock-based compensation.
Net Loss: The Company’s net loss was $19.1 million for the fourth quarter of 2018, compared to $24.0 million during the fourth quarter of 2017.

Financial Guidance

Intellia expects that its cash, cash equivalents and marketable securities as of December 31, 2018, as well as technology access and funding from Novartis and Regeneron, will enable Intellia to fund its anticipated operating expenses and capital expenditure requirements into the first half of 2021. This expectation excludes any potential milestone payments or extension fees that could be earned and distributed under the collaboration agreements with Novartis and Regeneron or any strategic use of capital not currently in the base-case planning assumptions.