On March 7, 2022 Alpine Immune Sciences, Inc. (NASDAQ: ALPN), a leading clinical-stage immunotherapy company focused on developing innovative treatments for cancer and autoimmune and inflammatory diseases, reported that the U.S. Food and Drug Administration (FDA) has placed a partial clinical hold on its NEON-2 trial evaluating davoceticept (ALPN-202) in combination with pembrolizumab in adults with advanced malignancies (Press release, Alpine Immune Sciences, MAR 7, 2022, View Source [SID1234609579]).

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The partial clinical hold was prompted by Alpine’s report of a Grade 5 serious adverse event (patient death) in the NEON-2 trial. The participant had choroidal melanoma previously treated with nivolumab and ipilimumab, and had received a single dose each of davoceticept and pembrolizumab. The participant’s death was attributed to cardiogenic shock, considered by the treating physicians as likely related to immune-mediated myocarditis, or possibly infection.

"Patient safety remains, as always, our top priority," said Mitchell H. Gold, Executive Chairman and Chief Executive Officer of Alpine. "We appreciate the dialogue with FDA and look forward to working diligently with FDA, Merck, the study Safety Monitoring Committee, and the study investigators to further understand this unfortunate event. Given the strong scientific rationale for the combination of davoceticept and pembrolizumab to benefit treatment-refractory patients, we are hopeful that the study will soon be resumed after appropriate safety review, and with appropriate safety precautions in place."

Patients currently enrolled in the NEON-2 trial may continue to receive davoceticept and pembrolizumab, although no additional patients may be enrolled until the partial clinical hold is resolved. The partial clinical hold does not affect the ongoing NEON-1 clinical trial of davoceticept as monotherapy (NCT04186637).

About Davoceticept (ALPN-202)

Davoceticept (ALPN-202) is a first-in-class, conditional CD28 costimulator and dual checkpoint inhibitor intended for the treatment of cancer. Preclinical studies of davoceticept have successfully demonstrated superior efficacy in tumor models compared to checkpoint inhibition alone. Completion of dose escalation and initiation of expansion cohorts of NEON-1 (NCT04186637), a Phase 1 monotherapy dose escalation and expansion trial in patients with advanced malignancies, is anticipated in the first half of 2022. NEON-2 (NCT04920383), a combination study of davoceticept (ALPN-202) and pembrolizumab was initiated in June 2021 and is currently on partial clinical hold as described above.

On March 7, 2022 Eagle Pharmaceuticals, Inc. (Nasdaq: EGRX) ("Eagle" or the "Company") reported financial results for the three and twelve months ended December 31, 2021 (Press release, Eagle Pharmaceuticals, MAR 7, 2022, View Source [SID1234609597]).

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Business and Recent Highlights:

Announced the commercial availability of its novel product, PEMFEXY (pemetrexed for injection), a branded alternative to ALIMTA. PEMFEXY is a ready-to-use liquid with a unique J-code and is approved in the United States to treat nonsquamous non-small cell lung cancer and mesothelioma. Eagle received approval from the U.S. Food and Drug Administration ("FDA") in February 2020 of its new drug application ("NDA") for PEMFEXY, following the settlement agreement of patent litigation with Eli Lilly and Company in December 2019. The agreement provided for a release of all claims by the parties and allows for an initial entry of PEMFEXY into the market (equivalent to approximately a three-week supply of ALIMTA utilization) on February 1, 2022, and a subsequent uncapped entry on April 1, 2022. The ALIMTA U.S. market totaled $1.2 billion for the 12 months ended December 31, 2021, as reported by Eli Lilly and Company
Commenced shipment of vasopressin on January 18, 2022 with 180 days of marketing exclusivity. Vasopressin, an A-rated generic alternative to Vasostrict, is indicated for use to increase blood pressure in adults with vasodilatory shock (e.g., post-cardiotomy or sepsis) who remain hypotensive despite fluids and catecholamines. U.S. sales of Vasostrict totaled $901.7 million for the 12 months ended December 31, 2021, as reported by Endo International plc.
AOP Orphan Pharmaceuticals GmbH, Member of the AOP Health Group, ("AOP Health"), with whom Eagle entered into a licensing agreement in August 2021, has engaged with the FDA to obtain alignment on the content and format of the pre-clinical and clinical data required to support an NDA seeking approval of Landiolol, a novel therapeutic, for the short-term reduction of ventricular rate in patients with supraventricular tachycardia, including atrial fibrillation and atrial flutter. Based on the FDA’s responses to AOP Health’s communications, Eagle remains on track to support AOP Health’s NDA filing for Landiolol in the second quarter of 2022.
1 The Company’s expectations with respect to the first quarter of 2022 are based on its estimates and assumptions as of March 7, 2022 and are subject to substantial uncertainty. The Company’s first quarter of 2022 is ongoing and not complete, and the Company’s expectations with respect to revenues, earnings per share and adjusted non-GAAP earnings per share for the first quarter of 2022 are estimates. Actual revenue, earnings per share and adjusted non-GAAP earnings per share for the Company’s first quarter of 2022 are subject to completion of the quarter as well as financial closing procedures for the period, and the actual and reported financial results for the Company’s first quarter of 2022 may materially differ. As such, the Company’s expectations with respect to the first quarter of 2022 are inherently unpredictable and actual results and outcomes could differ materially for a variety of reasons, including the factors discussed below under "Forward-Looking Statements".

* Adjusted non-GAAP net income, adjusted non-GAAP earnings per share, adjusted non-GAAP R&D expense and adjusted non-GAAP SG&A expense are non-GAAP financial measures. For descriptions and reconciliations of these non-GAAP financial measures to their most comparable GAAP financial measures, please see below and the tables at the end of this press release.

Financial Highlights

Fourth Quarter 2021

Total revenue for Q4 2021 was $42.3 million, compared to $49.9 million in Q4 2020, primarily reflecting lower product sales of BELRAPZO and RYANODEX and lower royalty revenue of BENDEKA, partially offset by higher product sales of TREAKISYM.
Q4 2021 net loss was $6.2 million, or $(0.48) per basic and diluted share, compared to net income of $8.1 million, or $0.62 per basic and $0.60 per diluted share, in Q4 2020.
Q4 2021 adjusted non-GAAP net income* was $11.2 million, or $0.87 per basic and $0.85 per diluted share, compared to adjusted non-GAAP net income* of $12.8 million, or $0.98 per basic and $0.96 per diluted share, in Q4 2020.
Cash and cash equivalents were $97.7 million, net accounts receivable was $41.1 million, and debt was $26.0 million as of December 31, 2021.
Full Year 2021

Total revenue for the 12 months ended December 31, 2021 was $171.5 million, compared to $187.8 million in 2020. 2020 included a $5.0 million milestone payment from SymBio Pharmaceuticals Limited for regulatory approval of TREAKISYM ready-to-dilute ("RTD") (250 ml) liquid bendamustine formulation.
Net loss for the 12 months ended December 31, 2021 was $8.6 million, or $(0.66) per basic and diluted share, compared to net income of $12.0 million, or $0.89 per basic and $0.87 per diluted share, in 2020.
Adjusted non-GAAP net income* for the 12 months ended December 31, 2021 was $34.4 million, or $2.64 per basic and $2.59 per diluted share, compared to $48.7 million, or $3.62 per basic and $3.54 per diluted share, in 2020.
From August 2016 through December 31, 2021, Eagle has repurchased $228.1 million of its common stock.
"With two important launches in early 2022, Eagle is off to a great start. The initial impressive revenue generated from vasopressin and PEMFEXY, each with significant periods of exclusivity, together with our royalties from bendamustine sales in Japan, position us to more than double our earnings this year. Based on early 2022 trends, we believe that our Q1 2022 earnings per share should approximate $4.00. Our pipeline is advancing as expected, and our balance sheet remains healthy. The period ahead will be exciting for us as we plan to deploy our cash to strengthen our product offerings and grow the company," stated Scott Tarriff, President and Chief Executive Officer of Eagle Pharmaceuticals.

Q4 2021 BELRAPZO product sales were $5.5 million, compared to $10.2 million in Q4 2020.

Q4 2021 RYANODEX product sales were $6.1 million, compared to $7.9 million in Q4 2020.

Royalty revenue was $26.2 million in the fourth quarter of 2021, compared to $27.0 million in the fourth quarter of 2020. BENDEKA royalties were $24.2 million in the fourth quarter of 2021, compared to $27.0 million in the fourth quarter of 2020.

Gross margin was 71% during the fourth quarter of 2021, as compared to 75% in the fourth quarter of 2020. The decrease in gross margin for the fourth quarter of 2021 was driven by revenue mix.

R&D expense was $3.8 million for the fourth quarter of 2021, compared to $9.4 million for the fourth quarter of 2020. The decrease was primarily due to the non-recurrence of development cost on vasopressin and lower spend on RYANODEX related projects. Excluding stock-based compensation and other non-cash and non-recurring items, adjusted non-GAAP R&D expense* during the fourth quarter of 2021 was $2.6 million.

SG&A expenses in the fourth quarter of 2021 totaled $20.3 million compared to $18.2 million in the fourth quarter of 2020. This increase was primarily related to employee related costs and consulting costs partially offset by a decrease in stock-based compensation expense. Excluding stock-based compensation and other non-cash and non-recurring items, fourth quarter 2021 adjusted non-GAAP SG&A expense* was $14.6 million.

Net loss for the fourth quarter of 2021 was $6.2 million, or $(0.48) per basic and diluted share, compared to net income of $8.1 million, or $0.62 per basic and $0.60 per diluted share, in the fourth quarter of 2020, as a result of the factors discussed above.

Adjusted non-GAAP net income* for the fourth quarter of 2021 was $11.2 million, or $0.87 per basic and $0.85 per diluted share, compared to adjusted non-GAAP net income* of $12.8 million or $0.98 per basic and $0.96 per diluted share in the fourth quarter of 2020.

Full Year 2021 Financial Results

Product sales decreased by $7.3 million in the year ended December 31, 2021, primarily driven by decreases in product sales of Bendeka by $4.3 million, coupled with decreases in Belrapzo product sales of $3.8 million, due to price decreases and Ryanodex product sales by $3.0 million, due to volume decreases. The decreased sales were partially offset by increases in product sales of $3.9 million for TREAKISYM.

Gross margin was 75% in 2021, as compared to 76% in 2020. The decrease in gross margin in 2021 was driven by revenue mix.

R&D expense increased to $51.3 million in 2021, compared to $30.8 million in 2020, primarily reflecting a $10.0 million upfront payment related to our license agreement with Combioxin SA for CAL02, a $5.0 million upfront payment related to our licensing agreement with AOP Orphan for Landiolol, and increases of $2.3 million in development costs for vasopressin, $2.1 million in employee related costs, and $1.6 million related to PEMFEXY launch preparedness and regulatory costs. Excluding stock-based compensation and other non-cash and non-recurring items, adjusted non-GAAP R&D expense* in 2021 was $32.5 million.

SG&A expenses decreased by $3.3 million to $75.3 million in 2021, compared to $78.6 million in 2020. The decrease primarily reflects lower stock-compensation expense and the non-recurrence of expense related to Tyme Technologies, Inc. ("Tyme"), partially offset by increases in external legal fees and employee related costs. Excluding stock-based compensation and other non-cash and non-recurring items, adjusted non-GAAP SG&A expense* in 2021 was $54.9 million.

Net loss for the year ended December 31, 2021 was $8.6 million, or $(0.66) per basic and diluted share, as compared to net income of $12.0 million or $0.89 per basic and $0.87 per diluted share for the year ended December 31, 2020, as a result of the factors discussed above.

Adjusted non-GAAP net income* for the year ended December 31, 2021 was $34.4 million, or $2.64 per basic and $2.59 per diluted share, compared to adjusted non-GAAP net income* of $48.7 million, or $3.62 per basic and $3.54 per diluted share, for 2020.

First Quarter 2022 Expected Revenue and EPS1

Revenue for the first quarter 2022 is expected to be in the range of $120 million – $130 million.
Adjusted non-GAAP earnings per share* for the first quarter 2022 is expected to be in the range of $3.80 – $4.10.
2022 Full Year Expense Guidance

Adjusted non-GAAP R&D expense* is expected to be in the range of $46 million to $50 million, as compared to $32.5 million in 2021.
Adjusted non-GAAP SG&A expense* is expected to be in the range of $54 million to $58 million, as compared to $54.9 million in 2021.
Liquidity

As of December 31, 2021, Eagle had $97.7 million in cash and cash equivalents plus $41.1 million in net accounts receivable, and $26.0 million in outstanding debt. Therefore, as of December 31, 2021, Eagle had net cash plus receivables of $112.8 million.

In the fourth quarter of 2021, Eagle purchased $8.6 million of its common stock as part of its current $160.0 million Share Repurchase Program. From August 2016 through December 31, 2021, Eagle has repurchased $228.1 million of its common stock.

Conference Call

As previously announced, Eagle management will host its fourth quarter 2021 conference call as follows:

A replay of the conference call will be available for one week after the call’s completion by dialing 800-839-0866 (US) or 402-220-0662 (International) and entering conference call ID EGRXQ421. The webcast will be archived for 30 days at the aforementioned URL.

On March 7, 2022 Nectin Therapeutics Ltd., (Nectin) a biotechnology company developing novel targeted immunotherapies that address resistance to approved immune oncology treatments, and Cancer Focus Fund, LP, a unique investment fund established in collaboration with The University of Texas MD Anderson Cancer Center (MD Anderson) to provide funding and clinical expertise to advance promising cancer therapies, reported a Cancer Focus Fund investment of $5.4 million to finance a Phase 1 clinical trial of Nectin’s PVR blocker, NTX1088, in cancer patients with locally advanced and metastatic solid tumors (Press release, Nectin Therapeutics, MAR 7, 2022, View Source [SID1234609616]).

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NTX1088 is a high affinity monoclonal antibody directed against PVR, an immune checkpoint ligand. NTX1088 blocks the signaling of the immune checkpoint receptors TIGIT and CD96, while restoring the expression and immune function of DNAM1 (CD226), resulting in increased anti-tumor immune effects from activated T cells and natural killer (NK) cells in the tumor microenvironment. PVR is overexpressed in many solid tumors across different cancer indications, including lung, colorectal, liver, ovarian, breast, adrenal, pancreatic, uterine, head and neck, gastric and esophageal. High PVR expression is associated with poor prognosis and with resistance to PD1 blockade, making PVR an attractive therapeutic target for novel immuno-oncology therapies, both as a monotherapy and in combination with PD1 blockers.

The Cancer Focus Fund investment will support a Phase 1 clinical study at MD Anderson, assessing NTX1088 in the treatment of locally advanced and metastatic solid tumors. Cancer Focus Fund is receiving a combination of equity and future payments from Nectin based on achievement of certain clinical and commercial milestones.

"Cancer Focus Fund is committed to advancing the clinical development of novel cancer therapies with the potential to have a significant impact on patients," said Ross Barrett, a founder and Managing Partner of Cancer Focus Fund. "Despite their early promise, the majority of cancer patients do not respond to, or eventually acquire resistance to, current immunotherapies. NTX1088 has a unique mechanism of action that works in three ways to suppress the immune inhibitory effects of tumors while also promoting direct anti-tumor activity. We are delighted to help fund this first-in-human clinical trial at MD Anderson, our collaborator in leading Cancer Focus Fund-financed clinical trials."

The Phase 1 trial is an open label study in 90 patients that will be conducted in two stages – a dose escalation stage and an expansion stage. NTX1088 will be investigated as a single agent and in combination with a PD1 blocker. The primary objectives of the dose escalation stage is to assess safety and tolerability and to select a recommended safe and effective dose. In the expansion stage of the trial, NTX1088’s safety and tolerability will be further evaluated, along with initial efficacy measures and exploratory assessments of pharmacodynamic and predictive biomarkers, which will assist in stratifying patients moving forward. Sarina A. Piha-Paul, MD, an Associate Professor in the Department of Investigational Cancer Therapeutics at MD Anderson, will serve as the Principal Investigator.

"Nectin Therapeutics is developing a portfolio of innovative anticancer compounds directed at highly differentiated targets within the nectin family of immune checkpoints," said Fabian Tenenbaum, Chief Executive Officer of Nectin Therapeutics. "The upcoming initiation of our first-in-human clinical trial is a major milestone for the company. We welcome the financial support from Cancer Focus Fund and clinical expertise of MD Anderson in facilitating the Phase 1 study for this promising new approach to helping patients mount an effective immune response to their cancer."

The Phase 1 trial is expected to begin enrolling patients around mid-year of 2022.

About NTX1088
NTX1088 is a first-in-class monoclonal antibody directed against a key immune checkpoint, PVR, also known as CD155. NTX1088 has a triple mechanism of action. It binds PVR with high affinity and blocks its interactions with TIGIT and CD96, preventing their immune inhibitory signaling. NTX1088 also blocks the interaction between PVR and DNAM1, also known as CD226, a molecule involved in the activation of anti-cancer T cells and NK cells. By preventing internalization and degradation of DNAM1, NTX1088 leads to restoration of DNAM1 expression on the surface of immune cells and results in robust antitumor activity. NTX1088 demonstrated superior antitumor activity compared to approved and investigational immune checkpoint inhibitors in preclinical models and revealed a favorable safety profile in non-human primates.

On March 7, 2022, UroGen Pharma Ltd. (the "Company"), UroGen Pharma, Inc., as the borrower (the "Borrower"), and certain direct and indirect subsidiaries of the Company party thereto from time to time, as guarantors (the "Guarantors" and, collectively with the Company and Borrower, the "Credit Parties") reported that entered into a loan agreement (the "Loan Agreement") with BPCR Limited Partnership (as a "Lender"), BioPharma Credit Investments V (Master) LP (as a "Lender"), and BioPharma Credit PLC, as collateral agent for the Lenders (in such capacity, the "Collateral Agent), pursuant to which the Lenders agreed to make term loans to the Borrower in an aggregate principal amount of up to $100,000,000 (the "Term Loans") (Filing, 8-K, UroGen Pharma, MAR 7, 2022, View Source [SID1234609654]). The proceeds of the Term Loans will be used to fund the Credit Parties’ general corporate and working capital requirements.

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Pursuant to the terms of the Loan Agreement, the Term Loans will be advanced in two tranches. The first tranche (the "Tranche A Loan") is expected to be advanced in the amount of $75,000,000, 10 business days following the effective date of the Loan Agreement ("Tranche A Closing Date"), subject to entering into security agreement and delivery of other customary deliverables. The second tranche (the "Tranche B Loan") of $25,000,000 will be advanced at the Borrower’s election, subject to the customary bring down conditions and deliverables, and in no event later than December 31, 2022. The Term Loans will mature on the 5th year anniversary of the Tranche A Closing Date ("Maturity Date").

The Term Loans bear interest at 8.25% plus three-month LIBOR per annum with a LIBOR floor of 1.25%. In the event of the cessation of LIBOR, the benchmark governing the interest rate will be replaced with a rate based on the secured overnight financing rate published by the Federal Reserve Bank of New York as described in the Loan Agreement. Interest is payable quarterly in arrears. Repayment of outstanding principal of the Term Loans will be made in four equal quarterly payments of principal commencing after the 17th-quarter anniversary of the Tranche A Closing Date.

The Borrower will pay to the Lenders a funding fee equal to 1.75% of the Lenders’ total committed amount to fund the Tranche A Loan and Tranche B Loan, payable on the Tranche A Closing Date. The Borrower may elect to prepay the Term Loans in whole prior to the Maturity Date with such prepayments being subject to a prepayment premium equal to the principal amount so prepaid multiplied by 3% if made prior to the 3rd anniversary of the Tranche A Closing Date, 2% if made on or after the 3rd anniversary of the Tranche A Closing Date but prior to the 4th anniversary of the Tranche A Closing Date, and 1% if made on or after the 4th anniversary of the Tranche A Closing Date but prior to the Maturity Date. In addition to the prepayment premium, prepayments of the Tranche A Loan prior to the 2nd anniversary of the Tranche A Closing Date and prepayments of the Tranche B Loan prior to the 2nd anniversary of the Tranche B Closing Date are subject to a makewhole amount equal to the sum of all interest that would have accrued through such 2nd anniversary. If the Term Loans are accelerated following the occurrence of an event of default, the Borrower shall immediately pay to Lenders the sum of all obligations for principal, interest, and the applicable makewhole and prepayment premium. The Borrower is also required to prepay the Term Loans upon a change of control and prior to certain prepayments or redemptions of permitted convertible debt, subject to exceptions for refinancings and conversions or exchanges for equity.

The obligations of the Borrower under the Loan Agreement are guaranteed on a full and unconditional basis by the Company and the other Guarantor and are secured by substantially all of the respective Credit Parties’ tangible and intangible assets and property, including intellectual property, subject to certain exceptions.

The Loan Agreement contains customary affirmative and restrictive covenants and representations and warranties. The Credit Parties are bound by certain affirmative covenants setting forth actions that are required during the term of the Loan Agreement, including, without limitation, certain information delivery requirements, obligations to maintain certain insurance, and certain notice requirements. Additionally, the Credit Parties are bound by certain restrictive covenants setting forth actions that are not permitted to be taken during the term of the Loan Agreement without Lender’s prior written consent, including, without limitation, (i) selling or disposing of assets, including certain intellectual property, (ii) amending, modifying or waiving certain material agreements or organizational documents, (iii) consummating certain change in control transactions, (iv) incurring certain additional indebtedness, (v) incurring any non-permitted lien or other encumbrance on the Credit Parties’ assets, (vi) paying dividends or making any distribution or payment on or redeeming, retiring or purchasing any equity interests, and (vii) making payments of certain subordinated indebtedness. The Loan Agreement does not contain any financial covenants. The Loan Agreement also contains the following customary events of default: (i)the Borrower’s failure to pay principal, interest and other amounts when due, (ii) the Credit Parties’ breach of the covenants under the Loan Agreement, (iii) the occurrence of a material adverse change, (iv) certain attachments of the Credit Parties assets and restraints on their business, (v) certain bankruptcy or insolvency events, (vi) cross-default of third-party indebtedness, (vii) the failure by the Credit Parties to pay judgements rendered against them, (viii) material misrepresentations, (ix) the loan documents ceasing to create a valid security interest in a material portion of the Collateral, (x) the occurrence of certain ERISA events, and (xi) a material default or breach under any intercreditor or subordination agreement by any parties thereto. Upon the occurrence of an event of default, the Lenders may, among other things, accelerate the Borrower’s obligations under the Loan Agreement.

On March 7, 2022 ("HUTCHMED") (Nasdaq/AIM:​HCM; HKEX:​13) reported that it has received a US$15 million milestone payment from AstraZeneca PLC ("AstraZeneca") (LSE/STO/Nasdaq:​AZN) (Press release, Hutchison China MediTech, MAR 7, 2022, View Source [SID1234609545]).

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This milestone has been triggered by the initiation of start-up activities for SAFFRON, the first global Phase III study for ORPATHYS in combination with TAGRISSO in epidermal growth factor receptor ("EGFR")-mutated non-small cell lung cancer ("NSCLC") patients with mesenchymal epithelial transition receptor ("MET") driven tumors following progression after TAGRISSO. SAFFRON, which is expected to commence enrolling patients in mid-2022, follows important lessons learned from the SAVANNAH study, which is targeted to be presented at an upcoming scientific conference in the second half of 2022.

To date, AstraZeneca has now paid HUTCHMED US$85 million of the total US$140 million in upfront payments, development and first-sale milestones due under the license and collaboration agreement between HUTCHMED and AstraZeneca.

About NSCLC, EGFR and MET Aberrations
Lung cancer is the leading cause of cancer death among men and women, accounting for about one-fifth of all cancer deaths.[1] More than a third of the world’s lung cancer patients are in China.[2] Lung cancer is broadly split into NSCLC and small cell lung cancer, with 80-85% classified as NSCLC.[3] The majority of NSCLC patients are diagnosed with advanced disease while approximately 25-30% present with resectable disease at diagnosis.[4],[5] For patients with resectable tumors, the majority of patients eventually develop recurrence despite complete tumor resection and adjuvant chemotherapy.[6]

Approximately 10-25% of NSCLC patients in the U.S. and Europe, and 30-40% of patients in Asia have EGFR-mutated NSCLC.[7],[8],[9] These patients are particularly sensitive to treatment with an EGFR tyrosine kinase inhibitor ("TKI") which blocks the cell-signaling pathways that drive the growth of tumor cells.[10]

MET is a tyrosine kinase receptor.[11] Aberration of MET (amplification or overexpression) is present in both treatment naïve patients as well as being one of the primary mechanisms of acquired resistance to EGFR TKIs for metastatic EGFR-mutated NSCLC.[12],[13] Approximately 2-3% of NSCLC patients have tumors with MET exon 14 skipping alterations, a targetable mutation in the MET gene.[14]

About Savolitinib (ORPATHYS in China)
Savolitinib is an oral, potent, and highly selective MET TKI that has demonstrated clinical activity in advanced solid tumors. It blocks atypical activation of the MET receptor tyrosine kinase pathway that occurs because of mutations (such as exon 14 skipping alterations or other point mutations) or gene amplification.

Savolitinib is marketed in China under the brand name ORPATHYS for the treatment of patients with NSCLC with MET exon 14 skipping alterations who have progressed following prior systemic therapy or are unable to receive chemotherapy. It is currently under clinical development for multiple tumor types, including lung, kidney, and gastric cancers, as a single treatment and in combination with other medicines.

In 2011, following its discovery and initial development by HUTCHMED, AstraZeneca and HUTCHMED entered a global licensing and collaboration agreement to jointly develop and commercialize savolitinib. Under the current terms of the agreement, a US$15 million milestone payment is triggered by the initiation of start-up activities for the SAFFRON study. Joint development of savolitinib in China is led by HUTCHMED, while AstraZeneca leads development outside of China. HUTCHMED is responsible for the marketing authorization, manufacturing and supply of savolitinib in China. AstraZeneca is responsible for the commercialization of savolitinib in China and worldwide. Sales of savolitinib are recognized by AstraZeneca.

Savolitinib development in NSCLC
Phase II study of savolitinib monotherapy in MET Exon 14 skipping alteration NSCLC (NCT02897479) – The conditional approval in China for MET Exon 14 skipping alteration NSCLC was based on the results of a Phase II study that were published in The Lancet Respiratory Medicine[15]. At a median follow up of 17.6 months, savolitinib demonstrated an objective response rate ("ORR") of 42.9% (95% confidence interval [CI] 31.1-55.3) and median progression-free survival ("PFS") of 6.8 months (95% CI 4.2-9.6) in the overall trial population. Disease control rate ("DCR") in the overall trial population was 82.9% (95% CI 72.0-90.8). The safety and tolerability profile of savolitinib was consistent with previous trials, and no new safety signals were identified. Continued approval is contingent upon the successful completion of a confirmatory trial in this patient population (NCT04923945).

Based on results of the TATTON and SAVANNAH studies below, several Phase III studies of savolitinib in combination with TAGRISSO have been initiated, including SACHI, and SANOVO and SAFFRON.

SACHI Phase III study of savolitinib in combination with TAGRISSO in patients who have progressed following EGFR TKI treatment due to MET amplification (NCT05015608) – Initiated in the second half of 2021, this is a randomized, open-label study in China in EGFR mutation positive NSCLC patients with MET amplified tumors following progression after treatment with any EGFR TKI.

SANOVO Phase III study of savolitinib in combination with TAGRISSO in treatment-naïve patients with EGFR mutant positive NSCLC with MET overexpression (NCT05009836) – Initiated in the second half of 2021, this is a randomized, blinded study in China in untreated, unresectable or metastatic patients with EGFR mutation positive NSCLC with MET positive tumors.

TATTON Phase Ib/II studies of savolitinib in combination with TAGRISSO in patients who have progressed following EGFR TKI treatment due to MET amplification (NCT02143466) – This global exploratory study in over 220 EGFR mutation positive NSCLC patients with MET amplified tumors following progression after treatment with any EGFR TKI. Results were published in Lancet Oncology[16] and final analysis was presented at the World Conference on Lung Cancer[17]. Three cohorts with patients treated following progression on first- or second-generation EGFR TKI demonstrated an ORR of 64.7-66.7% and a median PFS of 9.0-11.1 months. The cohort of patients treated following progression on a third-generation EGFR TKI demonstrated an ORR of 33.3% (95% CI 22.4-45.7), with a median PFS of 5.5 months (95% CI 4.1-7.7). The combination demonstrated encouraging anti-tumor activity and an acceptable risk-benefit profile.

SAVANNAH Phase II study of savolitinib in combination with TAGRISSO in patients who have progressed following TAGRISSO due to MET amplification or overexpression (NCT03778229) – This is a single-arm, open-label, global study in EGFR mutated NSCLC patients with MET amplified/overexpressed tumors following progression after treatment with TAGRISSO, an EGFR TKI owned by AstraZeneca. We plan to submit results for presentation at an upcoming scientific conference.

Savolitinib development in kidney cancer
SAMETA Phase III study in combination with IMFINZI PD-L1 inhibitor in MET-driven, unresectable and locally advanced or metastatic papillary renal cell carcinoma ("RCC") (NCT05043090) – Based on the encouraging results of the SAVOIR monotherapy and CALYPSO combination therapy studies below, we initiated SAMETA, a global Phase III, open-label, randomized, controlled study of savolitinib plus IMFINZI versus sunitinib monotherapy versus IMFINZI monotherapy in patients with MET-driven, unresectable and locally advanced or metastatic papillary RCC.

SAVOIR randomized, controlled study of savolitinib monotherapy in MET-driven PRCC (NCT03091192) – Data from 60 patients in this global study of savolitinib monotherapy compared with sunitinib monotherapy in MET-driven papillary RCC was presented at the ASCO (Free ASCO Whitepaper) 2020 Program and published simultaneously in JAMA Oncology[18]. Savolitinib demonstrated encouraging activity, including an ORR of 27% versus 7% for sunitinib, with no savolitinib responding patients experiencing disease progression at data cut-off, and an encouraging OS hazard ratio of 0.51 (95% CI: 0.21–1.17; p=0.110) with median not reached at data cut-off.

CALYPSO study of savolitinib in combination with IMFINZI PD-L1 inhibitor in RCC (NCT02819596) – This investigator initiated open-label Phase I/II study of savolitinib in combination with IMFINZI, a PD-L1 antibody owned by AstraZeneca, evaluated the safety and efficacy of the savolitinib/IMFINZI combination in patients with RCC. An analysis of 41 papillary RCC patients was presented at the 2021 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting[19], showing a confirmed response rate in 8 out of the 14 MET-driven patients, or 57%, with a median DoR of 9.4 months, median PFS of 10.5 months and median OS of 27.4 months. No new safety signals were seen.

Savolitinib development in gastric cancer and other cancer indications
Phase II study of savolitinib monotherapy in advanced or metastatic MET amplified gastric cancer ("GC") or adenocarcinoma of the gastroesophageal junction ("GEJ") (NCT04923932) – This is an open-label, two-cohort, multi-center study to evaluate the efficacy, safety and PK of savolitinib in locally advanced or metastatic GC or GEJ patients whose disease progressed after at least one line of standard therapy.

This trial follows multiple Phase II studies that have been conducted in Asia to study savolitinib in MET-driven GC patients, including VIKTORY[xx]. VIKTORY is an investigator-initiated Phase II umbrella study in GC in South Korea in which a total of 715 patients were successfully sequenced into molecular-driven patient groups, including those with MET amplified GC. Patients whose tumors harbor MET amplification were treated with savolitinib monotherapy, reporting an ORR of 50% (10/20, 95% CI: 28.0, 71.9).

Savolitinib opportunities are also continuing to be explored in multiple other MET-driven tumor settings via investigator-initiated studies including colorectal cancer.