Gilead Sciences 2021: Cushioned by COVID

Gilead’s top line in 2020 got help from an unexpected source – a failed developmental hepatitis C compound that turned out to be effective against COVID-19.

By Joshua Slatko • [email protected]

 

Gilead Sciences

333 Lakeside Drive

Foster City, CA 94404

Telephone: 650-574-3000

Website: gilead.com

 

OUTCOMES CREATIVITY INDEX SCORE: 10

Manny Awards — 5

Cannes Lions — N/A

Clio Health — 1

Creative Floor Awards — 4 

MM+M Awards — N/A

 

Financial Performance

(All figures are in millions of dollars, except EPS.)

2020  

Revenue $24,689  

Net income $89  

Diluted EPS $0.10  

R&D expense $5,039  

1H 2021  

Revenue $12,640  

Net income $3,239  

Diluted EPS $2.58  

R&D expense $2,189  

 

Best-Selling Products

(All sales are in millions of dollars.)

2020  

Biktarvy $7,259  

Genvoya $3,338  

Veklury $2,811  

Descovy $1,861  

Odefsey $1,672  

Sofosbuvir/Velpatasvir $1,599 

Truvada $1,448  

Vemlidy $657  

Yescarta $563  

1H 2021  

Biktarvy $3,818  

Veklury $2,285  

Genvoya $1,379  

Sofosbuvir/Velpatasvir $823  

Descovy $794  

Odefsey $749  

Vemlidy $381  

Yescarta $338  

Ambisome $277  

 

 

Of the COVID-19 pandemic had a silver lining for anyone in 2020, it was Gilead. As of January 1, the company’s compound remdesivir was nothing but another failed attempt at treatment for a variety of viral infections, not even worthy of a mention in Gilead’s 2019 annual report. By May, remdesivir had been granted emergency use authorization by FDA for the treatment of COVID-19 requiring hospitalization, and by the end of the year, under the brand name Veklury, the drug had generated nearly $3 billion in sales for Gilead, considerably more than the margin of growth between the company’s 2019 revenue and 2020. 

Gilead may have been lucky to stumble over a treatment for COVID already lurking in the company’s own medicine cabinet, but no luck was involved in rolling it out on the necessary grand scale. “It is remarkable that we are in this position today, given that remdesivir is such a complex medicine to manufacture with a typical lead time of nine to 12 months,” said CEO Daniel O’Day in October 2020. “Gilead has left no stone unturned in the efforts to bring us to this point. We invested in ramping up manufacturing long before we knew whether remdesivir would work, we brought on more than 40 additional manufacturing partners and our teams worked day and night to find ways to shorten the lead time, without compromising on safety or rigor.”

Gilead’s top-line revenue in 2020 was $24.69 billion, an improvement of 10 percent over the previous year. Net income, though, declined from $5.36 billion to $89 million, and earnings per share was down from $4.22 to 10 cents. This result, though, was impacted by a number of unusual circumstances, including unfavorable changes in the value of the company’s investment in Galapagos, a $1.2 billion tax benefit recorded in 2019 related to transfers of intangible assets to different tax jurisdictions, and expenses related to a number of acquisitions during the year, including Forty Seven and Immunomedics. On a pure operating basis, Gilead’s income from operations declined by just 5 percent in 2020, to $4.07 billion; company leaders estimated that earnings per share excluding the unusual items would have risen by 16 percent for the year. 

In the first half of 2021 Gilead’s top-line revenue rose another 18.2 percent to $12.64 billion, with net income returning to $3.24 billion and EPS of $2.58 per share after falling into the red in the first half of 2020. Company leaders are projecting that Gilead’s full-year earnings per share in 2021 will end up between $4.70 and $5.05. 

Partnerships & Acquisitions

In January, Gilead and Vir Biotechnology Inc. announced a clinical collaboration to evaluate novel therapeutic combination strategies aimed at developing a functional cure for chronic hepatitis B virus. The companies initiated a Phase II trial evaluating combination therapy for both treatment-experienced and treatment-naïve people living with HBV. The multi-arm trial is evaluating different combinations of selgantolimod, Gilead’s investigational TLR-8 agonist; VIR-2218, Vir’s investigational small interfering ribonucleic acid; and a commercially sourced, marketed PD-1 antagonist. People in the clinical trial with HBV treatment experience may also receive Gilead’s Vemlidy. 

The primary outcome of the study will be the proportion of patients achieving a functional cure, defined as an off-therapy loss of hepatitis B surface antigen and HBV DNA from the serum. Both companies retain full rights to their individual product candidates and will discuss the potential path forward for any future combination studies based on the outcome of the Phase II trial.

Also in January, Kite and Oxford BioTherapeutics Ltd., a clinical stage oncology company with a pipeline of immuno-oncology and antibody-drug conjugate-based drugs, announced a research collaboration to evaluate five novel targets for a number of hematologic and solid tumor indications. Through this collaboration, OBT will validate five novel oncology drug targets, previously identified using OBT’s OGAP discovery platform, and generate antibodies against these targets. Kite and Gilead will have the exclusive right to develop and commercialize therapies based on these targets or antibodies. 

Under the terms of the agreement, OBT received an upfront payment and will be eligible to receive additional payments based on achievement of certain discovery, clinical, and regulatory milestones, as well as royalties on future potential sales.

In February, Gilead and Gritstone Oncology Inc., a clinical stage biotech company developing next-generation cancer and infectious disease immunotherapies, announced a collaboration, option and license agreement to research and develop a vaccine-based immunotherapy as part of Gilead’s efforts to find a curative treatment for human immunodeficiency virus infection. 

Gilead and Gritstone will develop an HIV-specific therapeutic vaccine using Gritstone’s proprietary prime-boost vaccine platform, comprising self-amplifying mRNA (SAM) and adenoviral vectors, with antigens developed by Gilead. Under the terms of the agreement, Gilead made a $60 million payment at closing, consisting of a $30 million upfront cash payment and a $30 million equity investment at a premium. 

Gilead is responsible for conducting a Phase I study for the HIV-specific therapeutic vaccine and holds an exclusive option under the collaboration to obtain an exclusive license to develop and commercialize the HIV-specific therapeutic vaccine beyond Phase I. Gritstone is eligible to receive up to an additional $725 million if the option is exercised and if certain clinical, regulatory and commercial milestones are achieved, as well as mid single-digit to low double-digit tiered royalties on net sales upon commercialization.

In March, Gilead and Novo Nordisk A/S announced that the companies have expanded their clinical collaboration in non-alcoholic steatohepatitis. The companies will conduct a Phase IIb double-blind, placebo-controlled study to investigate the safety and efficacy of Novo Nordisk’s semaglutide, a GLP-1 receptor agonist, and a fixed-dose combination of Gilead’s investigational FXR agonist cilofexor and investigational ACC inhibitor firsocostat, alone and in combination in people with compensated cirrhosis (F4) due to NASH. The four-arm study in about 440 patients will evaluate the treatments’ impact on liver fibrosis improvement and NASH resolution and will begin recruitment in the second half of 2021.

This new Phase IIb study builds on positive results from a Phase IIa proof-of-concept study investigating semaglutide, alone and in combination with cilofexor and/or firsocostat, in 108 people with NASH and mild-to-moderate fibrosis. The study met its primary endpoint, demonstrating that all regimens were well tolerated over 24 weeks. In addition, post-hoc analyses of exploratory efficacy endpoints assessing biomarkers of liver health at 24 weeks showed statistically significant improvements in hepatic steatosis and liver injury in the combination treatment arms versus semaglutide alone. Liver stiffness and the Enhanced Liver Fibrosis score declined in all groups; however, statistically significant differences between groups were not observed.

Also in March, Gilead and Merck announced an agreement to jointly develop and jointly commercialize long-acting treatments in HIV that combine Gilead’s investigational capsid inhibitor lenacapavir, and Merck’s investigational nucleoside reverse transcriptase translocation inhibitor islatravir into a two-drug regimen with the potential to provide new, meaningful treatment options for people living with HIV. The first clinical studies of the oral combination are expected to begin in the second half of 2021. Under the terms of the agreement, Gilead and Merck will work as partners, sharing operational responsibilities, as well as development, commercialization and marketing costs, and any future revenues.

In June, Kite and Shoreline Biosciences Inc., a biotech company developing intelligently designed allogeneic off-the-shelf, standardized and targeted natural killer and macrophage cellular immunotherapies derived from induced pluripotent stem cells for cancer and other serious diseases, announced a strategic partnership to develop novel cell therapies across a variety of cancer targets.

According to company leaders, the collaboration will leverage Shoreline’s deep expertise in iPSC differentiation and genetic reprogramming in combination with Kite’s extensive cell therapy development, commercialization and manufacturing expertise to develop novel allogeneic candidates for a range of hematologic malignancies. The collaboration will focus initially on chimeric antigen receptor NK targets, with Kite having an option to expand the collaboration to include an iPSC CAR Macrophage program for an undisclosed target to be selected post deal execution. This agreement follows Kite’s investment in Shoreline’s recent Series A financing. Under the terms of the agreement, Shoreline received an upfront payment and will be eligible to receive additional payments totaling over $2.3 billion as well as royalties based on achievement of certain development and commercial milestones.

In August, the Gilead company Kite and Appia Bio Inc., an early-stage biotechnology company developing engineered allogeneic cell therapies from hematopoietic stem cells (HSCs) for cancer patients, announced a collaboration and license agreement to research and develop HSC-derived cell therapies directed toward hematological malignancies. Under the partnership, Kite and Appia Bio will develop chimeric antigen receptor (CAR)-engineered invariant natural killer T (CAR-iNKT) cells using Appia Bio’s ACUA technology platform for allogeneic cell therapy.

Under the terms of the agreement, Appia Bio is responsible for preclinical and early clinical research of two HSC-derived CAR-iNKT product candidates engineered with CARs provided by Kite. Appia Bio will receive an upfront payment, an equity investment, and additional milestone payments for a total value of up to $875 million as well as tiered royalties. Kite is responsible for the development, manufacturing, and commercialization of the product candidates identified through the collaboration.

Product Performance

The antiretroviral Biktarvy retained its title as the world’s leading HIV product with a bang in 2020, enjoying sales growth of 53.2 percent to $7.26 billion due to continued patient uptake. The growth has slowed somewhat in 2021, but first-half sales of Biktarvy still rose another 15.8 percent to $3.82 billion. Descovy, one of the ingredients of Biktarvy, also enjoyed solid growth in 2020, with sales up 24.1 percent to $1.86 billion due to growth of the Descovy for PrEP offering. 

In July, Gilead announced a pooled analysis of a 48-week open-label extension of two Phase III studies (Study 1489 and Study 1490) showing 99 percent of participants who initiated treatment with Biktarvy maintained an undetectable viral load (HIV-1 RNA <50 copies/mL) through four years of follow-up. In the 48-week open-label extension, there were zero cases of treatment-emergent resistance to any components of Biktarvy in participants treated with Biktarvy. These findings, along with long-term data from Phase III studies in virologically suppressed Black Americans and virologically suppressed people living with HIV aged 65 and older, demonstrated Biktarvy sustains efficacy with a high barrier to resistance across a range of people living with HIV, inclusive of their treatment history, gender, race or age. 

Gilead also presented long-term data from a Phase IIIb open-label trial enrolling people living with HIV aged 65 and older who switched to Biktarvy from either Genvoya or a tenofovir disoproxil fumarate-based regimen. The analysis showed that 100 percent of participants and 74 percent of participants in the snapshot analysis of the Intention to Treat-Exposed (ITT-E) population having HIV-1 RNA <50 copies/mL maintained high rates of virologic suppression at Week 96 with no virologic failures or emergent resistance through 96 weeks. The COVID-19 pandemic impacted in-person visits during the study, with 11 participants unable to be assessed after 84 weeks due to restrictions. There were two participants (2.3 percent) with Grade 3-4 study drug-related AEs, 11 participants (13 percent) with Grade 3-4 laboratory abnormalities, and three participants (3.51 percent) with drug-related adverse events leading to study drug discontinuation. These results reinforce Biktarvy as an effective and generally well-tolerated treatment option with a high barrier to resistance in the growing population of older people living with HIV.

Results from a Phase III study (Study 1844) demonstrated the safety and non-inferior efficacy of switching to Biktarvy in those replacing their existing treatment regimen. In Study 1844, participants who were virologically suppressed (HIV-1 RNA <50 copies/mL) on a regimen containing abacavir, dolutegravir, and lamivudine were randomly allocated and treated in a 1:1 ratio to stay on their existing regimen of ABC/DTG/3TC or switch to Biktarvy in a blinded manner. The primary endpoint was the proportion of patients with HIV RNA ≥50 copies/mL at Week 48. Study participants were randomly allocated through 48 weeks, after which point participants electing to continue in the study enter an open-label extension receiving Biktarvy. At the point of the last study visit, 98 percent of those who switched to Biktarvy maintained virologic suppression for a median duration of two years, including those with pre-existing resistance or who experienced viral “blips.” In participants treated with Biktarvy, there were no cases of treatment failure with resistance to any component of Biktarvy.

Coming from nowhere to leap to second place in Gilead’s portfolio, the COVID-19 treatment Veklury (remdesivir) generated $2.81 billion in sales for the company in 2020 and $2.29 billion during the first half of 2021. The antiviral drug had previously been studied in hepatitis C, Ebola and Marburg virus, but Veklury had never earned any approvals until FDA gave the green light for treating COVID requiring hospitalization during October 2020. Previously, an Emergency Use Authorization was granted by FDA for Veklury in May 2020. 

In June, Gilead announced positive data from three retrospective studies of the real-world treatment of patients hospitalized with COVID-19, adding to the body of mortality and hospital discharge data for patients treated with Veklury. All three of the real-world analyses observed that, in the overall patient populations, patients who received Veklury treatment had significantly lower risk for mortality compared with matched controls. A reduction in mortality was observed across a spectrum of baseline oxygen requirements. The results were consistently observed at different timeframes over the course of the pandemic and across geographies. Two of the studies also observed that patients who received Veklury had a significantly increased likelihood of discharge from the hospital by Day 28.

The Gilead/Kite lymphoma drug Yescarta generated sales of $563 million in 2020, a 23.5 percent improvement over the previous year. According to company leaders, this was due to continued uptake of Yescarta in Europe. In the first half of 2021, Yescarta sales rose another 14.2 percent to $338 million.

In February, Kite announced findings from a new analysis of the ZUMA-1 trial of Yescarta in adult patients with relapsed or refractory large B-cell lymphoma. In a new ZUMA-1 safety management cohort (Cohort 6), the primary objective was to assess the impact of prophylactic use of corticosteroids and earlier treatment with corticosteroids and/or tocilizumab on the incidence and severity of cytokine release syndrome and neurologic events. Patients with relapsed or refractory LBCL received dexamethasone 10 mg orally on the day of Yescarta infusion and each of the two following days. Corticosteroids and tocilizumab were started earlier, at lower grades of CRS and neurologic events, in Cohort 6 than in the ZUMA-1 pivotal cohorts (Cohorts 1 and 2). All 40 patients enrolled in Cohort 6 received at least one dose of corticosteroids.

In the Cohort 6 primary analysis, no Grade ≥3 CRS occurred. Grade ≥3 neurologic events occurred in 13 percent of patients and no patients experienced Grade 5 neurologic events at the time of data cut-off. Median time to onset of any grade CRS was five days and any grade neurologic events was six days. Sixty-eight percent of patients had no CRS or neurologic events within 72 hours of Yescarta infusion. Ninety-five percent of patients in Cohort 6 responded to Yescarta, including 80 percent of patients who achieved a complete response; 63 percent of patients were in an ongoing response at the time of the data cut-off (median study follow-up of 8.9 months).

In March, FDA granted accelerated approval to Yescarta for the treatment of adult patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy. The approval makes Yescarta the first chimeric antigen receptor T-cell therapy approved for patients with indolent follicular lymphoma.

The approval was based on results from ZUMA-5, a single-arm, open-label study in which 91 percent of patients with relapsed or refractory FL responded to Yescarta, including an estimated 74 percent of patients in a continued remission at 18 months (Kaplan-Meier estimate). Among all FL patients, median duration of response was not reached at a median follow-up of 14.5 months.

In June, Kite announced top-line results from the primary analysis of ZUMA-7, a randomized Phase III global, multicenter study showing superiority of Yescarta compared to standard of care in second-line relapsed or refractory large B-cell lymphoma. With a median follow-up of two years, the study met the primary endpoint of event-free survival. The study also met the key secondary endpoint of objective response rate.

Also in June, Fosun Kite Biotechnology Co., a joint venture between Kite and Shanghai Fosun Pharmaceutical (Group) Co., received approval from the China National Medical Products Administration for Yescarta for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy, including diffuse large B-cell lymphoma not otherwise specified, primary mediastinal large B-cell lymphoma, high-grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Yescarta is the first commercially available chimeric antigen receptor (CAR) T-cell therapy approved in China. The approval was based on results of a single-arm, open label, multi-center bridging trial (FKC876-2018-001) which has evaluated the efficacy and safety of FKC876 in the treatment of Chinese patients with refractory intermediate invasive non-Hodgkin’s lymphoma (NHL)/large B-cell lymphoma in China.

That same month, Kite announced follow-up results from the pivotal ZUMA-5 trial of Yescarta in patients with relapsed or refractory indolent follicular lymphoma. At a minimum follow-up of 18 months, 94 percent of patients had achieved a response, and secondary endpoints of median progression-free survival and overall survival were not yet reached. In a weighted analysis comparing ZUMA-5 patients with a minimum of 18 months follow-up with those observed in SCHOLAR-5, an external control cohort, Yescarta demonstrated superior OS and PFS over currently available treatments.

In The Pipeline

In February, Gilead and Galapagos NV announced the decision to halt the ISABELA Phase III clinical studies with the investigational autotaxin inhibitor ziritaxestat in patients with idiopathic pulmonary fibrosis. The decision was based on the recommendations of the Independent Data Monitoring Committee which, following a regular review of unblinded data, concluded that ziritaxestat’s benefit-risk profile no longer supported continuing these studies.

In April, FDA granted accelerated approval of Trodelvy (sacituzumab govitecan-hziy) for use in adults with locally advanced or metastatic urothelial cancer who have previously received a platinum-containing chemotherapy and either a programmed death receptor-1 or a programmed death-ligand 1 inhibitor. The accelerated approval was based on data from the international Phase II, single-arm TROPHY study. Of the 112 patients who were evaluable for efficacy, 27.7 percent of those treated with Trodelvy responded to treatment, with 5.4 percent experiencing a complete response and 22.3 percent experiencing a partial response. The median duration of response was 7.2 months. Trodelvy was acquired by Gilead in October 2020 in the Immunomedics transaction. 

In June, Gilead completed submission of a New Drug Application to FDA seeking approval of lenacapavir, an investigational, long-acting HIV-1 capsid inhibitor, for the treatment of HIV-1 infection in heavily treatment-experienced (HTE) people with multi-drug resistant (MDR) HIV-1 infection. A similar application was validated by the European Medicines Agency in August.

The submission was supported by data from the Phase II/III CAPELLA trial, which evaluated the safety and efficacy of lenacapavir administered subcutaneously every six months in combination with an optimized antiretroviral background regimen. The study achieved its primary endpoint by demonstrating that a significantly higher proportion of participants randomly allocated to receive lenacapavir achieved a clinically meaningful viral load reduction of at least 0.5 log10 copies/mL from baseline compared with those receiving placebo during the 14-day functional monotherapy period (88 percent versus 17 percent).

Also in June, Gilead announced interim results from the Phase IIb and Phase III clinical trials evaluating the first-in-class entry inhibitor Hepcludex (bulevirtide) for the treatment of chronic hepatitis delta virus. Findings from the Phase III study support the safety and efficacy profile of Hepcludex 2 mg once daily. Results from the Phase IIb trial show that treatment with Hepcludex alone or in combination with peginterferon alfa-2a, is associated with a significant HDV RNA decline and improvements in biochemical disease activity at Week 24. Hepcludex joined Gilead’s portfolio when the company completed the acquisition of MYR GmbH in March. 

The Phase III data will be included in the filing of Hepcludex to FDA during 2021. Hepcludex has been granted Breakthrough Therapy Designation and Orphan Drug status by FDA and been granted Conditional Marketing Authorization by the European Commission and PRIority MEdicines (PRIME) scheme eligibility by the European Medicines Agency as the first approved treatment in Europe for adults with chronic HDV and compensated liver disease.

Interim results from the Phase III MYR301 study indicate that after 24 weeks, the proportion of people with HDV achieving the combined virological and biochemical response was 36.7 percent with Hepcludex 2 mg, 28 percent in participants receiving Hepcludex 10 mg, and 0 percent in participants currently under observation who have not received antiviral treatment at this stage of the study. Treatment for 24 weeks with Hepcludex 2 mg or 10 mg had a superior response to the no treatment group, with Hepcludex 2 mg for 24 weeks having a numerically higher response rate compared with Hepcludex 10 mg. Additionally, rapid ALT reduction and normalization were observed in more than 50 percent of patients in the Hepcludex 2 mg group compared with the Hepcludex 10 mg or no treatment groups.

Also in June, FDA approved an expansion of the pediatric indication of Epclusa for the treatment of chronic hepatitis C virus to now include children as young as 3 years of age, regardless of HCV genotype or liver disease severity. FDA approved a New Drug Application for two strengths of an oral pellet formulation of Epclusa (sofosbuvir 200 mg/velpatasvir 50 mg and sofosbuvir 150 mg/velpatasvir 37.5 mg) developed for use by younger children who cannot swallow tablets.

The approval of Epclusa for children as young as 3 years of age was based on data from a Phase II, open-label clinical trial that enrolled 41 children 3 years to less than 6 years of age to be treated with Epclusa for 12 weeks. At 12 weeks after treatment completion, Epclusa achieved a sustained virologic response (SVR12) or cure rate of 83 percent among all patients, 88 percent in children with HCV genotype 1, 50 percent in children with HCV genotype 2, and 100 percent in children with HCV genotype 3 and HCV genotype 4. Of the seven patients who did not achieve cure, all discontinued treatment within one to 20 days of starting treatment.

That same month, Kite announced results from the primary analysis of ZUMA-3, a global, multicenter, single-arm, open-label Phase I/II study evaluating its chimeric antigen receptor T-cell therapy Tecartus (brexucabtagene autoleucel) in adult patients with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. In the pivotal Phase II portion of the trial, 71 patients with relapsed or refractory disease were enrolled. Among treated patients, 47 percent had received three or more prior therapies. At a median follow-up of 16.4 months, 71 percent of treated patients achieved a complete response or CR with incomplete hematological recovery, with 31 percent in ongoing response at data cut-off. 97 percent of those responders had deep molecular remission, with undetectable minimal residual disease, and median overall survival among all responders was not reached. Among 25 patients with prior blinatumomab treatment, the CR/CRi rate was 60 percent. Among all treated patients, median duration of response, relapse-free survival, and OS were 12.8 months, 11.6 months, and 18.2 months, respectively. FDA has accepted a supplemental Biologics License Application and granted Priority Review designation for Tecartus for the treatment of adult patients with relapsed or refractory B-cell precursor ALL.

Also during June, Gilead announced new data from the Phase III ASCENT study evaluating Trodelvy in relapsed or refractory metastatic triple-negative breast cancer. In this subgroup analysis of brain metastases-negative patients who received only one line of prior systemic therapy in the metastatic setting in addition to having disease recurrence or progression within 12 months of (neo)adjuvant chemotherapy, Trodelvy improved progression-free survival, with a 59 percent reduction in the risk of disease worsening or death and a median PFS of 5.7 months versus 1.5 months with chemotherapy. Trodelvy also extended median overall survival to 10.9 months versus 4.9 months with chemotherapy.

In September, Gilead announced new data from the ASCENT study evaluating Trodelvy in patients with relapsed or refractory metastatic triple-negative breast cancer who received two or more prior systemic therapies, at least one of them for metastatic disease. In a retrospective subgroup analysis, Trodelvy improved progression-free survival, overall survival, and objective response rate compared with chemotherapy chosen by the patients’ physicians in patients who were not initially diagnosed with TNBC.

This analysis included 146 chemotherapy-eligible brain metastasis-negative patients with an original breast cancer diagnosis that was not TNBC, of which 70 received Trodelvy and 76 received physician’s choice of chemotherapy. Among these patients, Trodelvy improved median PFS compared with chemotherapy (4.6 months versus 2.3 months), median OS (12.4 months versus 6.7 months) and ORR (31 percent versus 4 percent). Outcomes were similar to those of the overall ASCENT trial population.