On October 30, 2020 Ligand Pharmaceuticals Incorporated (NASDAQ: LGND) reported financial results for the three- and nine-months ending September 30, 2020 and provided an operating forecast and program updates (Press release, Ligand, OCT 30, 2020, View Source [SID1234569477]). Ligand management will host a conference call with slides today beginning at 8:30 a.m. Eastern time to discuss this announcement and answer questions.

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"Our business is performing very well across the board. We are pleased to be reporting strong third quarter financial results and foresee substantial momentum and accelerating growth as we close out 2020 and move into 2021," said John Higgins, Chief Executive Officer of Ligand. "Revenue is tracking well against the guidance we raised throughout the year, and we are pleased with our earnings performance with adjusted diluted EPS coming in much higher than our outlook at the start of 2020."

Higgins continued, "Beyond robust financial performance, we closed three acquisitions in the past three months, with Pfenex in particular providing significant P&L contribution and a major new technology platform backed by top-tier partnering contracts. We are proud of our contribution to helping make Gilead’s Veklury possible as the first and only FDA approved treatment for COVID-19. Our core business is very strong and forms the foundation of Ligand’s value, but we certainly see the surge in Captisol business due to Veklury as meaningful upside now and over the next few quarters. Captisol material sales will provide Ligand increased cash flow and, in turn, the opportunity to invest in other areas to drive future growth."

Third Quarter 2020 Financial Results

Total revenues for the third quarter of 2020 were $41.8 million, compared with $24.8 million for the same period in 2019. Royalties for the third quarter of 2020 were $9.0 million, compared with $9.8 million for the same period in 2019. Royalties for the third quarter of 2020 and 2019 primarily consisted of royalties from Kyprolis and EVOMELA. Captisol sales were $23.4 million for the third quarter of 2020, compared with $6.8 million for the same period in 2019, primarily reflecting higher sales of Captisol for use with remdesivir. Contract revenue was $9.5 million for the third quarter of 2020, compared with $8.2 million for the same period in 2019.

Cost of goods sold was $6.4 million for the third quarter of 2020, compared with $3.1 million for the same period in 2019, with the increase primarily attributable to higher sales of Captisol. Amortization of intangibles was $3.9 million for the third quarter of 2020, compared with $3.6 million for the same period in 2019, with the increase attributable to the Icagen acquisition in April 2020. Research and development expense was $12.9 million for the third quarter of 2020, compared with $13.7 million for the same period of 2019, with the decrease primarily attributable to amortization of research and development expense related to Novan and Palvella in the prior-year period. General and administrative expense was $15.0 million for the third quarter of 2020, compared with $9.5 million for the same period in 2019, with the increase primarily attributable to additional expenses from Icagen and other acquisition-related cost.

Net loss for the third quarter of 2020 was $6.7 million, or $0.42 per share, compared with net loss of $15.3 million, or $0.81 per share, for the same period in 2019. Net loss for the third quarter of 2020 included a $11.7 million net non-cash loss from the value of Ligand’s short-term investments, while net loss for the third quarter of 2019 included a $13.4 million net non-cash loss from the value of Ligand’s short-term investments. Adjusted net income for the third quarter of 2020 was $17.5 million, or $1.04 per diluted share, compared with $9.5 million, or $0.49 per diluted share, for the same period in 2019. Please see the table below for a reconciliation of net income/(loss) to adjusted net income.

As of September 30, 2020, Ligand had cash, cash equivalents and short-term investments of $795 million. Following the closing of the Pfenex acquisition on October 1, Ligand had approximately $400 million in cash, cash equivalents and short-term investments.

Year-to-Date Financial Results

Total revenues for the nine months ended September 30, 2020 were $116.4 million, compared with $93.3 million for the same period in 2019. Royalties for the nine months ended September 30, 2020 were $22.8 million and primarily consisted of royalties from Kyprolis and EVOMELA. Royalties for the nine months ended September 30, 2019 were $35.9 million and included $14.2 million in royalties from Promacta; Ligand sold its Promacta license to Royalty Pharma as of March 6, 2019. Captisol sales were $69.0 million for the nine months ended September 30, 2020, compared with $24.4 million for the same period in 2019, with the increase primarily reflecting higher sales of Captisol for use with remdesivir. Contract revenue was $24.7 million for the nine months ended September 30, 2020, compared with $33.0 million for the same period in 2019, with the change due to the timing of partner events.

Cost of goods sold was $18.7 million for the nine months ended September 30, 2020, compared with $9.4 million for the same period in 2019, with the increase primarily attributable to higher sales of Captisol. Amortization of intangibles for the nine months ended September 30, 2020 was $11.3 million, compared with $10.6 million for the same period in 2019, with the increase attributable to the Icagen acquisition. Research and development expense was $37.5 million for the nine months ended September 30, 2020, compared with $37.2 million for the same period of 2019. General and administrative expense was $34.4 million for the nine months ended September 30, 2020, compared with $31.6 million for the same period in 2019, with the increase primarily attributable to additional expenses from Icagen and other acquisition-related costs.

Net loss for the nine months ended September 30, 2020 was $8.7 million, or $0.54 per share, compared with net income of $636.7 million, or $31.29 per diluted share, for the same period in 2019. Net loss for the nine months ended September 30, 2020 included a net non-cash loss in the value of Ligand’s short-term investments of $17.9 million, while net income for the same period in 2019 was impacted by an after-tax gain of approximately $643 million on the sale of the Promacta license. Adjusted net income for the nine months ended September 30, 2020 was $49.4 million, or $2.93 per diluted share, compared with $48.2 million, or $2.37 per diluted share, for the same period in 2019. Please see the table below for a reconciliation of net income/(loss) to adjusted net income.

2020 and 2021 Financial Guidance

Ligand reiterates 2020 financial guidance and 2021 financial guidance newly introduced at its Analyst Day event on October 20, 2020, as follows:

For 2020, Ligand expects total revenue to be approximately $170 million and adjusted diluted EPS to be $3.95. Total revenue is expected to consist of $92 million in Captisol sales, $33 million in royalty revenue and $45 million in contract revenue.
For 2021, Ligand expects total revenue to be approximately $285 million and adjusted diluted EPS to be $6.00. Total revenue is expected to consist of $200 million of Captisol sales, $45 million in royalty revenue and $40 million in contract revenue.
Third Quarter 2020 and Recent Business Highlights

OmniAb Platform Updates

OmniAb is Ligand’s multi-species antibody platform for the discovery of mono- and bi-specific therapeutic human antibodies. As of the third quarter of 2020, more than 8,500 clinical subjects have been or are planned to be treated by partners in clinical trials with OmniAb-derived antibodies. New clinical programs are pending at Johnson & Johnson and Merck, among others. Ligand expects the first regulatory submission for OmniAb-derived antibodies in 2021, with potential for as many as 10 approvals expected by 2025.

As part of the OmniAb platform, Ligand recently announced OmniTaur, featuring Ultralong CDR-H3 humanized binding domains recently acquired from Taurus Biosciences. The OmniAb platform also includes the ultra-high resolution, high-speed automated antibody selection technology acquired from xCella Biosciences.

Multiple OmniAb partners reported clinical or regulatory progression with OmniAb-derived antibodies during the third quarter. Additionally, three Ligand partners (Takeda, Immunoprecise and Genovac) are pursuing development of therapeutic antibodies for the treatment of COVID-19 that were discovered with OmniAb.

CStone Pharmaceuticals announced the formation of a $480 million strategic collaboration that encompasses a $200 million equity investment by Pfizer Hong Kong in CStone, collaboration between CStone and Pfizer Investment for the development and commercialization of CStone’s PD-L1 antibody sugemalimab (CS1001) in mainland China and a framework between CStone and Pfizer Investment to bring additional oncology assets to the Greater China market. CStone announced updated results from two clinical studies of sugemalimab at the 2020 Chinese Society of Clinical Oncology Annual Meeting. CStone announced that sugemalimab met the primary endpoint as first-line treatment in stage IV squamous and non-squamous non-small cell lung cancer.

Immunovant announced positive topline results from a multicenter, placebo-controlled Phase 2a trial (ASCEND MG) of IMVT-1401, a novel investigational anti-FcRn antibody delivered by subcutaneous injection, in patients with myasthenia gravis (MG). A registration-enabling Phase 3 MG trial is expected to initiate in the first half of 2021.

Captisol Business Updates

To date in 2020, Ligand has entered into more than 120 Captisol research use agreements and eight clinical and/or commercial license agreements. This is the highest number of use agreements to be signed in a single year since the invention of Captisol.

Captisol is utilized in the formulation of Gilead Sciences’ Veklury (remdesivir), which on October 22, 2020 received U.S. Food and Drug Administration (FDA) approval for the treatment of patients with COVID-19 requiring hospitalization. The product has regulatory approvals for the treatment of moderate or severe COVID-19 in over 50 countries and is included in more than 30 ongoing clinical trials. Ligand is supplying Captisol to Gilead under a recently signed 10-year supply agreement. Ligand is also supplying Captisol to Gilead’s voluntary licensing generic partners who are manufacturing remdesivir for 127 low- and middle-income countries.

Partner Marinus was recently awarded a BARDA contract by the U.S. government to develop Captisol-enabled IV ganaxolone for the treatment of refractory status epilepticus (RSE) caused by nerve agent exposure. Marinus also announced it had satisfied the FDA protocol-specific questions for the registrational Phase 3 trial (the RAISE trial) in RSE, allowing the company to begin patient enrollment in October. Topline data are anticipated in the first half of 2022.

Ligand plans to initiate a potentially pivotal trial for Captisol-enabled Iohexol (CE-Iohexol) in December 2020. CE-Iohexol is an iodine-based contrast agent for hospital-based imaging procedures.

Protein Expression Technology Platform Updates

On October 1, Ligand closed the previously announced acquisition of Pfenex, Inc. Pfenex brings to Ligand a proprietary protein expression technology, as well as major collaborations with Jazz Pharmaceuticals, Merck, Serum Institute of India and Alvogen, each of which has potential to contribute meaningfully to Ligand’s royalty revenue. Our partner Merck announced positive data from two Phase 3 studies with V114, which uses the protein expression technology, evaluating the safety, tolerability and immunogenicity of the investigational 15-valent pneumococcal conjugate vaccine with plans for global regulatory licensure applications in the fourth quarter 2020. Also using the platform, Jazz Pharmaceutical’s Erwinaze supply challenges due to issues with their manufacturer were solved, resulting in a robust process showing manufacturing consistency and efficiency. The program was completed from commencement to projected first BLA filing in approximately four years.

Ligand entered into a new 10-year CRM197 supply agreement with a global multi-national pharmaceutical partner focused on vaccine development.

Other Business Updates

Ligand announced the sale of its Vernalis research operations and internal programs to HitGen Inc. for $25 million in cash. Under the terms of the agreement, Ligand will retain economic rights on completed collaboration licenses as well as a share of the economic rights on current research collaboration contracts. The transaction is expected to close in the fourth quarter of 2020, subject to customary closing conditions.

Several partners also had significant regulatory, financing and business updates during the third quarter: Verona Pharma announced initiation of its ENHANCE Phase 3 trials, Retrophin announced enrollment of the first 280 patients in the pivotal Phase 3 PROTECT study of sparsentan in IgA nephropathy, and Sermonix Pharmaceuticals announced a collaboration with Eli Lilly to study lasofoxifene in combination with Lilly’s CDK 4 and 6 inhibitor abemaciclib in metastatic breast cancer.

Ligand provides regular updates on individual partner events through its Twitter account, @Ligand_LGND.

Adjusted Financial Measures

The Company reports adjusted net income and adjusted net income per diluted share in addition to, and not as a substitute for, or superior to, financial measures calculated in accordance with GAAP. The Company’s financial measures under GAAP include share-based compensation expense, amortization of debt-related costs, amortization related to acquisitions and intangible assets, changes in contingent liabilities, mark-to-market adjustments for amounts relating to its equity investments in public companies, excess tax benefit from share-based compensation, gain on the sale of Promacta and others that are listed in the itemized reconciliations between GAAP and adjusted financial measures included at the end of this press release. However, other than with respect to total revenues, the Company only provides financial guidance on an adjusted basis and does not provide reconciliations of such forward-looking adjusted measures to GAAP due to the inherent difficulty in forecasting and quantifying certain amounts that are necessary for such reconciliation, including adjustments that could be made for changes in contingent liabilities, changes in the market value of its investments in public companies, stock-based compensation expense and effects of any discrete income tax items. Management has excluded the effects of these items in its adjusted measures to assist investors in analyzing and assessing the Company’s past and future core operating performance. Additionally, adjusted earnings per diluted share is a key component of the financial metrics utilized by the Company’s board of directors to measure, in part, management’s performance and determine significant elements of management’s compensation.

Conference Call

Ligand management will host a conference call with slides today beginning at 8:30 a.m. Eastern time (5:30 a.m. Pacific time) to discuss this announcement and answer questions. To participate via telephone, please dial (833) 325-0071 from the U.S. or (720) 405-1612 from outside the U.S., using the conference ID 9279386. To participate via live or replay webcast, a link is available at www.ligand.com. Slides to accompany the conference call are available here.

About OmniAb

OmniAb is a multi-species transgenic-animal platform consisting of six different technologies used for producing mono- and bispecific human therapeutic antibodies. OmniRat animals comprise the industry’s first human monoclonal antibody technology based on rats. Because they have a complete immune system with a diverse antibody repertoire, OmniRat animals generate antibodies with human idiotypes as effectively as wild-type animals make rat antibodies. OmniMouse is a transgenic mouse that complements OmniRat and expands epitope coverage. OmniFlic is an engineered rat with a fixed light chain for development of bispecific, fully human antibodies. OmniChicken animals comprise the industry’s first human monoclonal antibody technology based on chickens. The OmniClic chicken is specifically developed to facilitate the generation of bispecific antibodies and retains the ability to generate diverse, high quality affinity matured antibodies. All five types of OmniAb therapeutic human antibody platform, OmniRat, OmniFlic, OmniMouse, OmniChicken, OmniClic and OmniTaur, use patented technology, have broad freedom to operate, produce highly diversified, fully human antibody repertoires optimized in vivo for immunogenicity, manufacturability, and therapeutic efficacy, and deliver fully human antibodies with high affinity, specificity, expression, solubility and stability – Naturally Optimized Human Antibodies.

About Captisol

Captisol is a patent-protected, chemically modified cyclodextrin with a structure designed to optimize the solubility and stability of drugs. Captisol was invented and initially developed by scientists in the laboratories of Dr. Valentino Stella, University Distinguished Professor at the University of Kansas’ Higuchi Biosciences Center for specific use in drug development and formulation. This unique technology has enabled several FDA-approved products, including Gilead’s VEKLURY, Amgen’s KYPROLIS, Baxter International’s NEXTERONE, Acrotech Biopharma L.L.C.’s and CASI Pharmaceuticals’ EVOMELA, Melinta Therapeutics’ BAXDELA and Sage Therapeutics’ ZULRESSO. There are many Captisol-enabled products currently in various stages of development. Ligand maintains a broad global patent portfolio for Captisol with more than 400 issued patents worldwide relating to the technology (including 37 in the U.S.) and with the latest expiration date in 2033. Other patent applications covering methods of making Captisol, if issued, extend to 2040.

Protein Expression Technology Platform

The Protein Expression Technology is a robust, validated, cost-effective and scalable platform for recombinant protein production, and is especially well-suited for complex, large-scale protein production where traditional systems are not suitable. Multiple global manufacturers have demonstrated consistent success with the platform and the technology is currently out-licensed for numerous commercial and development-stage programs. The versatility of the platform has been demonstrated in the production of enzymes, peptides, antibody derivatives and engineered non-natural proteins. Partners seek the platform as it can contribute significant value to biopharmaceutical development programs by reducing development timelines and costs for manufacturing therapeutics and vaccines. Given pharmaceutical industry trends toward large molecules with increasing structural complexities, the Protein Expression Technology is well positioned to meet these growing needs as the most comprehensive broadly available protein production platform in the industry.

On October 30, 2020 Jounce Therapeutics, Inc. (NASDAQ: JNCE), a clinical-stage company focused on the discovery and development of novel cancer immunotherapies and predictive biomarkers, reported that it will report third quarter 2020 financial results and provide a corporate update before market open on Friday, November 6, 2020 (Press release, Jounce Therapeutics, OCT 30, 2020, View Source [SID1234569476]). Jounce Therapeutics’ management team will host a live conference call and webcast at 8:00 a.m. ET.

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Conference Call and Webcast
To access the conference call, please dial (866) 916-3380 (domestic) or (210) 874-7772 (international) and refer to conference ID 8009939. The live webcast can be accessed under "Events & Presentations" in the Investors and Media section of the company’s website at www.jouncetx.com. The webcast will be archived and made available for replay on the company’s website approximately two hours after the call and will be available for 30 days thereafter.

On October 30, 2020 Genmab A/S (Nasdaq: GMAB) and ADC Therapeutics SA (NYSE: ADCT) reported that they have executed an amended agreement for ADC Therapeutics to continue the development and commercialization of camidanlumab tesirine (Cami) (Press release, Genmab, OCT 30, 2020, View Source [SID1234569474]).

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The parties first entered into a collaboration and license agreement in June 2013 for the development of Cami, an antibody drug conjugate (ADC) which combines Genmab’s HuMax-TAC antibody targeting CD25 with ADC Therapeutics’ highly potent pyrrolobenzodiazepine (PBD) warhead technology. Under the terms of the 2013 agreement, the parties were to determine the path forward for continued development and commercialization of Cami upon completion of a Phase 1a/b clinical trial. ADC Therapeutics previously announced that Cami achieved an overall response rate of 86.5%, including a complete response rate of 48.6%, in Hodgkin lymphoma patients in this trial who had received a median of five prior lines of therapy.

Cami is currently being evaluated in a 100-patient pivotal Phase 2 clinical trial intended to support the submission of a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA). The trial is more than 50 percent enrolled and ADC Therapeutics anticipates reporting interim results in the first half of 2021.

"We have a long-standing relationship with the ADC Therapeutics team and believe they are an ideal partner for the ongoing development and potential commercialization of Cami," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab. "We look forward to the continued advancement of this CD25-targeted ADC."

"We are delighted to have reached an agreement with Genmab which will allow ADC Therapeutics to leverage the hematology-focused commercial organization we are building in the U.S. for our lead program loncastuximab tesirine (Lonca) in non-Hodgkin lymphoma," said Chris Martin, Chief Executive Officer of ADC Therapeutics. "When we started collaborating with Genmab on the development of Cami in 2013, ADC Therapeutics was a startup. Since that time, our team has grown significantly to encompass all aspects of ADC research and development. The U.S. commercial organization, including a hematology sales force, that we are establishing will position us strongly for the commercialization of Cami, if approved."

Under the terms of the amended and restated license agreement, the parties have agreed to eliminate the defined divestment process which was agreed in 2013 and that envisaged, among other things, offering the opportunity for third parties to continue the development and commercialization of Cami. The parties have also agreed, among other things, that Genmab will convert its economic interest in Cami into a mid-to-high single-digit tiered royalty on net sales.

About Camidanlumab Tesirine (Cami)
Camidanlumab tesirine (Cami, formerly ADCT-301) is an antibody drug conjugate (ADC) comprised of a human monoclonal antibody that binds to CD25 (HuMax-TAC, licensed from Genmab A/S), conjugated to the pyrrolobenzodiazepine (PBD) dimer payload, tesirine. Once bound to a CD25-expressing cell, ADCT-301 is internalized into the cell where enzymes release the PBD-based warhead killing the cell. This applies to CD25-expressing tumor cells, and also to CD25-expressing Tregs. The intra-tumoral release of its PBD warhead may also cause bystander killing of neighboring tumor cells and PBDs have also been shown to induce immunogenic cell death. All of these properties of Cami may enhance immune-mediated anti-tumor activity. Cami is being evaluated in a pivotal Phase 2 clinical trial in patients with relapsed or refractory Hodgkin lymphoma (HL), as well as in a Phase 1a/1b clinical trial in patients with relapsed or refractory HL and non-Hodgkin lymphoma and a Phase 1b clinical trial as monotherapy, and with a planned arm in combination with pembrolizumab, in solid tumors.

On October 30, 2020 Kazia Therapeutics Limited (ASX: KZA; NASDAQ: KZIA), an Australian oncology-focused biotechnology company, reported an update on the ongoing development of its product candidates for the quarter ending 30 September 2020 (Press release, Kazia Therapeutics, OCT 30, 2020, View Source [SID1234569471]).

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Key Points

Paxalisib granted special designations by US FDA: Rare Pediatric Disease Designation in DIPG, Orphan Designation in glioma, and Fast Track Designation in glioblastoma

New clinical collaboration launched with Dana-Farber Cancer Institute: a phase II study in primary CNS lymphoma, led by Dr Lakshmi Nayak

Post-period: completion of a ~$25 million financing round and execution of definitive agreement with GCAR to commence GBM AGILE pivotal study

Kazia CEO, Dr James Garner, commented, "the September quarter has been highly productive: we have launched a new clinical study, and we have seen important recognition by FDA of the drug’s potential in several forms of brain cancer. These achievements leave us ideally positioned as we now transition into the GBM AGILE pivotal study in glioblastoma. The remainder of this year, and the year ahead, are likely to be rich in data read-outs and in operational progress, as we see paxalisib move rapidly towards commercialization."

FDA Special Designations Awarded

In August 2020, Kazia received Rare Pediatric Disease Designation (RPDD) from the US FDA for paxalisib in the treatment of diffuse intrinsic pontine glioma (DIPG). RPDD is designed to support and encourage the development of drugs for rare childhood illnesses. The key benefit of it the program is that it allows for the sponsor company to receive a priority review voucher (PRV) at the time of an application for marketing authorization in the paediatric disease. The PRV can be sold to another company and used for any new drug, and such transactions have historically commanded prices between US$ 68 and 350 million.

Also in August 2020, Kazia received Fast Track Designation (FTD) from the US FDA for paxalisib in the treatment of glioblastoma. FTD is designed to expedite development of pharmaceutical products which demonstrate the potential to address unmet medical needs in serious or life-threatening conditions. It provides Kazia with substantially enhanced access to FDA, including the ability to submit a ‘rolling NDA’, in which components of the new drug application can be filed as they become available, increasing efficiency and reducing risk in the approval process.

In addition, and also in August 2020, Kazia received Orphan Drug Designation (ODD) from the US FDA for paxalisib in the treatment of glioma. This encompasses both DIPG and glioblastoma. The company previously received ODD for the narrower indication of glioblastoma in February 2018. ODD provides access to certain grant funding, a waiver of PDUFA fees at the time of NDA submission (currently approximately US$ 3 million per indication), and a period of data exclusivity which augments the patent protection.

The achievement of these milestones leaves the paxalisib program well-optimised from a regulatory standpoint:-

Glioblastoma

DIPG

Orphan Drug Designation February 2018 August 2020
Fast Track Designation August 2020
Rare Pediatric Disease Designation n/a August 2020
New Phase II Study in Primary CNS Lymphoma

In September 2020, Kazia launched a new clinical collaboration with Dana Farber Cancer Institute. Under the terms of the collaboration, Dr Lakshmi Nayak will lead a phase II investigator-initiated clinical trial in primary CNS lymphoma. Dr Nayak is an extensively published clinical researcher in this field, and Dana Farber has a world-leading specialist unit for treatment and research of this disease. Primary CNS lymphoma is a form of brain cancer that affects approximately 1,500 patients per annum in the United States. It is considered a high-potential target for paxalisib, since three of the four FDA-approved PI3K inhibitors are used to treat forms of lymphoma outside the central nervous system.

Broad Clinical Trial Program on Track

Sponsor
Phase

Indication

Registration

Kazia Therapeutics

II

Glioblastoma

NCT03522298

Alliance for Clinical Trials in Oncology

II

Brain metastases

NCT03994796

Dana-Farber Cancer Institute

II

Breast cancer brain metastases

(with Herceptin)

NCT03765983

Dana-Farber Cancer Institute

II

Primary CNS lymphoma

TBD

St Jude Children’s Research Hospital

DIPG (childhood brain cancer)

NCT03696355

Memorial Sloan Kettering Cancer Center

Brain metastases

(with radiotherapy)

NCT04192981

Post-Period Events – Successful Capital Raise

On 1 October 2020, Kazia launched a one-for-three accelerated non-renounceable entitlement offer to raise approximately $25 million, before fees. The transaction was fully-underwritten by Bell Potter Securities Limited. The accelerated institutional component closed on 2 October 2020, raising approximately $16.4 million from institutional investors, representing approximately a 70% take-up. The retail component closed on 20 October 2020, raising a further $8.8 million, with approximately 32% take-up.

This financing leaves the company well-funded to execute the GBM AGILE pivotal study.

Post-Period Events – GBM AGILE Moves into Operational Phase

On 16 October 2020, the company executed a definitive agreement with the Global Coalition for Adaptive Research (GCAR) to commence paxalisib’s participation in the GBM AGILE pivotal study in glioblastoma.

GBM AGILE is an international, multi-drug platform study, designed to expedite the approval of new medicines for glioblastoma. It is run independently of any individual company, under the leadership of some of the world’s premier experts in the field. The study is already ongoing, with thirty sites in the United States and Canada participating, and the first drug is Bayer’s Stivarga (regorafenib). Paxalisib will be the second drug to enter the study. First patient in to the paxalisib arm is expected to occur in early Q1 CY2021.

Impact of COVID-19

The company has no revisions to its prior guidance concerning COVID-19. At present, there is limited operational impact, but Kazia continues to monitor the situation closely.

Financial Update

As noted in the accompanying Appendix 4C, the company’s cash position as at 30 September 2020 was AU$ 6.5 million. The company invested AU$ 1.6 million in research and development activities during 1Q FY2021, and incurred G&A expenses of AU$ 0.6 million.

On the basis of cash at 30 September 2020 and expenditure during the quarter, the Appendix 4C reflects almost three quarters of available funding. However, immediately post-period, the company executed a fully underwritten capital raise which yielded approximately $25 million in new capital, before fees. As a consequence, the company’s operations are well-funded for the foreseeable future.

Upcoming Milestones

The key milestones for the next two quarters are as follows:-

Additional interim data from the ongoing phase II study of paxalisib in glioblastoma (November 2020 – SNO Annual Meeting)

Initial interim data from the ongoing phase I study of paxalisib in DIPG at St Jude Children’s Research Hospital (November 2020 – SNO Meeting)

Initial interim data from the ongoing phase II study in breast cancer brain metastases at Dana-Farber Cancer Institute (precise timing remains uncertain due to COVID-related disruption of conference schedules)

Top-line final data from the completed phase I study of Cantrixil in ovarian cancer

First patient in (FPI) to GBM AGILE registration study for paxalisib in glioblastoma (planned for each Q1 CY2021 in order to avoid Christmas and New Year period)

These milestones are indicative and may be subject to change.

On October 30, 2020 Novartis reported the receipt of marketing authorization from Japan’s Ministry of Health, Labor and Welfare (MHLW) for Foundation for Biomedical Research and Innovation at Kobe ("FBRI") to manufacture and supply commercial Kymriah (tisagenlecleucel) for patients in Japan (Press release, Novartis, OCT 30, 2020, View Source [SID1234569468]). This approval makes FBRI the first and only approved commercial manufacturing site for CAR-T cell therapy in Asia.

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"Behind our efforts to reimagine medicine with CAR-T cell therapy lies a commitment to build a manufacturing network that brings treatment closer to patients," commented Steffen Lang, Global Head of Novartis Technical Operations. "The expertise and infrastructure of FBRI, a world-leading manufacturing organization, allows us to bring CAR-T manufacturing to Asia. With the Japan MHLW commercial manufacturing approval, the recent capacity expansion in the US and our ongoing efforts to optimize and evolve our processes, we are well-positioned to deliver this potentially curative treatment option to more patients around the world."

Novartis has the largest geographical CAR-T cell therapy manufacturing network in the world, including seven CAR-T manufacturing facilities, across four continents. Commercial manufacturing for Kymriah now takes place at five sites globally including at the Morris Plains, New Jersey facility, where the US Food and Drug Administration (FDA) recently approved a further increase in manufacturing capacity.

Kymriah is the first-ever FDA-approved CAR-T cell therapy, and the first-ever CAR-T to be approved in two distinct indications. It is a one-time treatment designed to empower patients’ immune systems to fight their cancer. Kymriah is currently approved for the treatment of r/r pediatric and young adult (up to 25 years of age) acute lymphoblastic leukemia (ALL), and r/r adult diffuse large B-cell lymphoma (DLBCL)1. Kymriah, approved in both indications by the Japan MHLW in 2019, is currently the only CAR-T cell therapy approved in Asia. Clinical manufacturing began at FBRI in 2019 and will continue alongside commercial manufacturing.

Kymriah was developed in collaboration with the Perelman School of Medicine at the University of Pennsylvania, a strategic alliance between industry and academia, which was first-of-its-kind in CAR-T research and development.

About Novartis Commitment to Oncology Cell & Gene
Novartis has a mission to reimagine medicine by bringing curative cell & gene therapies to patients worldwide. Novartis has a deep CAR-T pipeline and ongoing investment in manufacturing and supply chain process improvements. With active research underway to broaden the impact of cell and gene therapy in oncology, Novartis is going deeper in hematological malignancies, reaching patients with other cancer types and evaluating next-generation CAR-T cell therapies that focus on new targets and utilize new technologies.

Novartis was the first pharmaceutical company to significantly invest in pioneering CAR-T research and initiate global CAR-T trials. Kymriah, the first approved CAR-T cell therapy, developed in collaboration with the Perelman School of Medicine at the University of Pennsylvania, is the foundation of Novartis’ commitment to CAR-T cell therapy. Kymriah is currently approved for use in at least one indication in 26 countries and at more than 260 certified treatment centers, with the ambition for further expansion to help fulfill the ultimate goal of bringing CAR-T cell therapy to every patient in need.

The Novartis global CAR-T manufacturing footprint spans seven facilities, across four continents. This comprehensive, integrated footprint strengthens the flexibility, resilience and sustainability of the Novartis manufacturing and supply chain. Commercial and clinical trial manufacturing is now ongoing at Novartis-owned facilities in Stein, Switzerland, Les Ulis, France and Morris Plains, New Jersey, USA, as well as at the contract manufacturing sites at Fraunhofer-Institut for cell therapy and immunology (Fraunhofer-Institut für Zelltherapie und Immunologie) facility in Leipzig, Germany, and now FBRI in Kobe, Japan. Manufacturing production at Cell Therapies in Australia and Cellular Biomedicine Group in China is forthcoming.

Important Safety information from the Kymriah SmPC

EU Name of the medicinal product:

Kymriah 1.2 x 106 – 6 x 108 cells dispersion for infusion

Important note: Before prescribing, consult full prescribing information.

Presentation: Cell dispersion for infusion in 1 or more bags for intravenous use (tisagenlecleucel).

Indications: Treatment of pediatric and young adult patients up to and including 25 years of age with B-cell acute lymphoblastic leukemia (ALL) that is refractory, in relapse post‑transplant or in second or later relapse. Treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy.

Dosage and administration:

B-cell patients: For patients 50 kg and below: 0.2 to 5.0 x 106 CAR-positive viable T-cells/kg body weight. For patients above 50 kg: 0.1 to 2.5 x 108 CAR-positive viable T-cells (non-weight based).

DLBCL Patients: 0.6 to 6.0×108 CAR-positive viable T-cells (non-weight based).

Pre‑treatment conditioning (lymphodepleting chemotherapy): Lymphodepleting chemotherapy is recommended to be administered before Kymriah infusion unless the white blood cell (WBC) count within one week prior to infusion is ≤1,000 cells/μL. The availability of Kymriah must be confirmed prior to starting the lymphodepleting regimen.

Precautions before handling or administering Kymriah: Kymriah contains genetically modified human blood cells. Healthcare professionals handling Kymriah should therefore take appropriate precautions (wearing gloves and glasses) to avoid potential transmission of infectious diseases.

Preparation for infusion
The timing of thaw of Kymriah and infusion should be coordinated. Once Kymriah has been thawed and is at room temperature (20°C ‑25°C), it should be infused within 30 minutes to maintain maximum product viability, including any interruption during the infusion.

Administration
Kymriah should be administered as an intravenous infusion through latex‑free intravenous tubing without a leukocyte depleting filter, at approximately 10 to 20 mL per minute by gravity flow. If the volume of Kymriah to be administered is ≤20 mL, intravenous push may be used as an alternative method of administration.

All contents of the infusion bag(s) should be infused.

Clinical assessment prior to infusion: Kymriah treatment should be delayed in some patient groups at risk (see Special warnings and precautions for use).

Monitoring after infusion: Patients should be monitored daily for the first 10 days following infusion for signs and symptoms of potential cytokine release syndrome, neurological events and other toxicities. Physicians should consider hospitalisation for the first 10 days post infusion or at the first signs/symptoms of CRS and/or neurological events. After the first 10 days following the infusion, the patient should be monitored at the physician’s discretion. Patients should be instructed to remain within proximity of a qualified clinical facility for at least 4 weeks following infusion.

Elderly (above 65 years of age): Safety and efficacy have not been established in B-cell patients. No dose adjustment is required in patients over 65 years of age in DLBCL patients.

Paediatric patients: No formal studies have been performed in paediatric patients with B-cell ALL below 3 years of age. The safety and efficacy of Kymriah in children and adolescents below 18 years of age have not yet been established in DLBCL. No data are available.

Patients seropositive for hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV): There is no experience with manufacturing Kymriah for patients with a positive test for HIV, active HBV, or active HCV infection. Leukapheresis material from these patients will not be accepted for Kymriah manufacturing.

Contraindications: Hypersensitivity to the active substance or to any of the excipients of Kymriah. Contraindications of the lymphodepleting chemotherapy must be considered.

Warnings and precautions: Reasons to delay treatment: Due to the risks associated with Kymriah treatment, infusion should be delayed if a patient has any of the following conditions: Unresolved serious adverse reactions (especially pulmonary reactions, cardiac reactions or hypotension) from preceding chemotherapies, active uncontrolled infection, active graft versus host disease (GVHD), significant clinical worsening of leukaemia burden or rapid progression of lymphoma following lymphodepleting chemotherapy. Blood, organ, tissue and cell donation: Patients treated with Kymriah should not donate blood, organs, tissues or cells.

Active central nervous system (CNS) leukaemia or lymphoma: There is limited experience of use of Kymriah in patients with active CNS leukaemia and active CNS lymphoma. Therefore the risk/benefit of Kymriah has not been established in these populations. Risk of CRS: Occurred in almost all cases within 1 to 10 days post infusion with a median time to onset of 3 days and a median time to resolution of8 days. See full prescribing information for management algorithm of CRS. Risk of neurological events: Majority of events, in particular encephalopathy, confusional state or delirium, occurred within 8 weeks post infusion and were transient. The median time to onset of neurological events was 8 days in B-cell ALL and 6 days in DLBCL; the median time to resolution was 7 days for B-cell ALL and 13 days for DLBCL. Patients should be monitored for neurological events. Risk of infections: Delay start of therapy with Kymriah until active uncontrolled infections have resolved. As appropriate, administer prophylactic antibiotics and employ surveillance testing prior to and during treatment with Kymriah. Serious infections were observed in patients, some of which were life threatening or fatal. After Kymriah administration observe patient and ensure prompt management in case of signs of infection Risk of febrile neutropenia: Frequently observed after Kymriah infusion, may be concurrent with CRS. Appropriate management necessary. Risk of prolonged cytopenias: Appropriate management necessary. Prolonged cytopenia has been associated with increased risk of infections. Myeloid growth factors, particularly granulocyte macrophage colony stimulating factor (GM CSF), not recommended during the first 3 weeks after Kymriah infusion or until CRS has been resolved. Risk of secondary malignancies: Patients treated with Kymriah may develop secondary malignancies or recurrence of their cancer and should be monitored life‑long for secondary malignancies. Risk of hypogammaglobulinemia or agammaglobulinemia: Infection precautions, antibiotic prophylaxis and immunoglobulin replacement should be managed per age and standard guidelines. In patients with low immunoglobulin levels preemptive measures such as immunoglobulin replacement and rapid attention to signs and symptoms of infection should be implemented. Live vaccines: The safety of immunisation with live viral vaccines during or following Kymriah treatment was not studied. Vaccination with live virus vaccines is not recommended at least 6 weeks prior to the start of lymphodepleting chemotherapy, during Kymriah treatment, and until immune recovery following treatment with Kymriah. Risk of tumor lysis syndrome (TLS): Patients with elevated uric acid or high tumor burden should receive allopurinol or alternative prophylaxis prior to Kymriah infusion. Continued monitoring for TLS following Kymriah administration should also be performed. Concomitant disease: Patients with a history of active CNS disorder or inadequate renal, hepatic, pulmonary or cardiac function are likely to be more vulnerable to the consequences of the adverse reactions of Kymriah and require special attention. Prior stem cell transplantation: Kymriah infusion is not recommended within 4 months of undergoing an allogeneic stem cell transplant (SCT) because of potential risk of worsening GVHD. Leukapheresis for Kymriah manufacturing should be performed at least 12 weeks after allogeneic SCT. Serological testing: There is currently no experience with manufacturing Kymriah for patients testing positive for HBV, HCV and HIV. Screening for HBV, HCV and HIV, must be performed before collection of cells for manufacturing. Hepatitis B virus (HBV) reactivation, can occur in patients treated with medicinal products directed against B cells and could result in fulminant hepatitis, hepatic failure and death. Prior treatment with anti CD19 therapy: There is limited experience with Kymriah in patients exposed to prior CD19 directed therapy. Kymriah is not recommended if the patient has relapsed with CD19 negative leukaemia after prior anti-CD19 therapy. Interference with serological testing: Due to limited and short spans of identical genetic information between the lentiviral vector used to create Kymriah and HIV, some commercial HIV nucleic acid tests (NAT) may give a false positive result. Sodium and potassium content: This medicinal product contains 24.3 to 121.5 mg sodium per dose, equivalent to 1 to 6% of the WHO recommended maximum daily intake of 2 g sodium for an adult. This medicinal product contains potassium, less than 1 mmol (39 mg) per dose, i.e. essentially "potassium free". Content of dextran 40 and dimethyl sulfoxide (DMSO): Contains 11 mg dextran 40 and 82.5 mg dimethyl sulfoxide (DMSO) per mL. Each of these excipients are known to possibly cause anaphylactic reaction following parenteral administration. Patients not previously exposed to dextran and DMSO should be observed closely during the first minutes of the infusion period.

Interaction with other medicinal products and other forms of interaction

Live vaccines: The safety of immunisation with live viral vaccines during or following Kymriah treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during Kymriah treatment, and until immune recovery following treatment with Kymriah.

Fertility, pregnancy and lactation

Women of childbearing potential/Contraception in males and females: Pregnancy status for females of reproductive potential should be verified prior to starting treatment with Kymriah. Consider the need for effective contraception in patients who receive the lymphodepleting chemotherapy. There are insufficient exposure data to provide a recommendation concerning duration of contraception following treatment with Kymriah.

Pregnancy: There are no data from the use of Kymriah in pregnant women. It is not known whether Kymriah has the potential to be transferred to the foetus via the placenta and could cause foetal toxicity, including B cell lymphocytopenia. Kymriah is not recommended during pregnancy and in women of childbearing potential not using contraception. Pregnant women should be advised on the potential risks to the foetus. Pregnancy after Kymriah therapy should be discussed with the treating physician. Pregnant women who have received Kymriah may have hypogammaglobulinaemia. Assessment of immunoglobulin levels is indicated in newborns of mothers treated with Kymriah.

Breast feeding: It is unknown whether Kymriah cells are excreted in human milk, a risk to the breast fed infant cannot be excluded. Women who are breast feeding should be advised of the potential risk to the breast fed infant. Breast-feeding should be discussed with the treating physician.

Fertility: There are no data on the effect of Kymriah on fertility.

Effects on ability to drive and use machines
Driving and engaging in hazardous activities in the 8 weeks following infusion should be refrained due to risks for altered or decreased consciousness or coordination.

Adverse drug reactions:

B-Cell ALL patients and DLBCL patients:

Very common (≥10%): Infections – pathogen unspecified, viral infections, bacterial infections, fungal infections, anaemia, haemorrhage, febrile neutropenia, neutropenia, thrombocytopenia, cytokine release syndrome, hypogammaglobulinaemia, decreased appetite, hypokalaemia, hypophosphataemia, hypomagnesaemia, hypocalcaemia, anxiety, delirium, sleep disorder, headache, encephalopathy, arrhythmia, hypotension, hypertension, cough, dyspnoea, hypoxia, diarrhoea, nausea, vomiting, constipation, abdominal pain, rash, arthralgia, acute kidney injury, pyrexia, fatigue, oedema, pain, chills, lymphocyte count decreased, white blood cell count decreased, haemoglobin decreased, neutrophil count decreased, platelet count decreased, aspartate aminotransferase increased.

Common (1 to 10%): Haemophagocytic lymphohistiocytosis, leukopenia, pancytopenia, coagulopathy, lymphopenia, infusion-related reactions, graft versus host disease, hypoalbuminaemia, hyperglycaemia, hyponatraemia, hyperuricaemia, fluid overload, hypercalcemia, tumor lysis syndrome, hyperkalaemia, hyperphosphataemia, hypernatraemia, hypermagnesaemia, dizziness, peripheral neuropathy, tremor, motor dysfunction, seizure, speech disorder, neuralgia, ataxia, visual impairment, cardiac failure, cardiac arrest, thrombosis, capillary leak syndrome, oropharyngeal pain, pulmonary oedema, nasal congestion, pleural effusion, tachypnea, acute respiratory distress syndrome, stomatitis, abdominal distension, dry mouth, ascites, hyperbilirubinaemia, pruritus, erythema, hyperhidrosis, night sweats, back pain, myalgia, muscolosceletal pain, influenza-like illness, asthenia, multiple organ dysfunction syndrome, alanine aminotransferase increased, blood bilirubin increased, weight decreased, serum ferritin increased, blood fibrinogen decreased, international normalized ratio increased, fibrin D dimer increased, activated partial thromboplastin time prolonged, blood alkaline phosphate increased, prothrombin time prolonged.

Uncommon: B-cell aplasia, ischaemic cerebral infarction, flushing, lung infiltration.

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