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Risk of hepatitis B reactivation and cytomegalovirus related infections with Mogamulizumab: A retrospective study of international pharmacovigilance database

Mish Boyka

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1. Introduction

Adult T cell leukemia/lymphoma (ATL), a rare and aggressive malignancy, can be classified into four clinical subtypes: acute, lymphoma, chronic, and smoldering types based on presenting features [

1

Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984–87).

 

]. First-line treatment encompasses high-intensity chemotherapy combination with good response. However, for relapsed/refractory cases, the treatment options are limited [

2

  • Pui C.H.
  • Robison L.L.
  • Look A.T
Acute lymphoblastic leukaemia.

 

]. Advanced stage cutaneous T cell lymphomas (CTCL) also pose significant treatment challenge to physicians [

3

Jacobsen ED and Weinstock DM, 2018. Challenges and implications of genomics for T-cell lymphomas. Hematology 2014, the American Society of Hematology Education Program Book, 2018(1), pp. 63–68.

 

]. Novel targeted medications have been studied actively in the past 20 years, with some of them showing a significant survival benefit in these conditions [

4

  • El Hajj H.
  • Tsukasaki K.
  • Cheminant M.
  • Bazarbachi A.
  • Watanabe T.
  • Hermine O.
Novel treatments of adult T cell leukemia lymphoma.

 

,

5

  • Bazarbachi A.
  • Suarez F.
  • Fields P.
  • Hermine O.
How I treat adult T-cell leukemia/lymphoma.

 

]. Mogamulizumab (Moga), a defucosylated humanized monoclonal antibody against C C chemokine receptor 4 (CCR4) [

6

  • Yamamoto K.
  • Utsunomiya A.
  • Tobinai K.
  • Tsukasaki K.
  • Uike N.
  • Uozumi K.
  • Yamaguchi K.
  • Yamada Y.
  • Hanada S.
  • Tamura K.
  • Nakamura S.
Phase I study of KW-0761, a defucosylated humanized anti-CCR4 antibody, in relapsed patients with adult T-cell leukemia-lymphoma and peripheral T-cell lymphoma.

 

], has been approved for the treatment of CCR4-positive relapsed/refractory ATL in Japan in 2012[

7

  • Yu X.
  • Marshall M.J.
  • Cragg M.S.
  • Crispin M.
Improving antibody-based cancer therapeutics through glycan engineering.

 

]. And, further approved for CCR4-positive relapsed/refractory CTCL in 2014 [

7

  • Yu X.
  • Marshall M.J.
  • Cragg M.S.
  • Crispin M.
Improving antibody-based cancer therapeutics through glycan engineering.

 

]. In the United States, the Food and Drug Administration (FDA) approved Moga for the treatment of relapsed/refractory mycosis fungoides and Sézary syndrome in 2018 []. The phase I and phase II clinical trials illustrated the efficacy of Moga in treating both ATL and CTCL with tolerable toxicities [

6

  • Yamamoto K.
  • Utsunomiya A.
  • Tobinai K.
  • Tsukasaki K.
  • Uike N.
  • Uozumi K.
  • Yamaguchi K.
  • Yamada Y.
  • Hanada S.
  • Tamura K.
  • Nakamura S.
Phase I study of KW-0761, a defucosylated humanized anti-CCR4 antibody, in relapsed patients with adult T-cell leukemia-lymphoma and peripheral T-cell lymphoma.

 

,

9

  • Ishida T.
  • Joh T.
  • Uike N.
  • Yamamoto K.
  • Utsunomiya A.
  • Yoshida S.
  • Saburi Y.
  • Miyamoto T.
  • Takemoto S.
  • Suzushima H.
  • Tsukasaki K.
Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: a multicenter phase II study.

 

,

10

  • Ogura M.
  • Ishida T.
  • Hatake K.
  • Taniwaki M.
  • Ando K.
  • Tobinai K.
  • Fujimoto K.
  • Yamamoto K.
  • Miyamoto T.
  • Uike N.
  • Tanimoto M.
Multicenter phase II study of mogamulizumab (KW-0761), a defucosylated anti-cc chemokine receptor 4 antibody, in patients with relapsed peripheral T-cell lymphoma and cutaneous T-cell lymphoma.

 

,

11

  • Ishida T.
  • Jo T.
  • Takemoto S.
  • Suzushima H.
  • Uozumi K.
  • Yamamoto K.
  • Uike N.
  • Saburi Y.
  • Nosaka K.
  • Utsunomiya A.
  • Tobinai K.
Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T‐cell leukaemia‐lymphoma: a randomized phase II study.

 

]. In one phase II clinical trial in ATL patients, overall response rate (ORR) was observed to be 50%, whereas – progression free survival (PFS) and overall survival (OS) was 5.2 and 13.7 months respectively [

6

  • Yamamoto K.
  • Utsunomiya A.
  • Tobinai K.
  • Tsukasaki K.
  • Uike N.
  • Uozumi K.
  • Yamaguchi K.
  • Yamada Y.
  • Hanada S.
  • Tamura K.
  • Nakamura S.
Phase I study of KW-0761, a defucosylated humanized anti-CCR4 antibody, in relapsed patients with adult T-cell leukemia-lymphoma and peripheral T-cell lymphoma.

 

]. Another phase II clinical trial demonstrated an objective response of 35% and PFS of 3 months in CTCL post-Moga [

10

  • Ogura M.
  • Ishida T.
  • Hatake K.
  • Taniwaki M.
  • Ando K.
  • Tobinai K.
  • Fujimoto K.
  • Yamamoto K.
  • Miyamoto T.
  • Uike N.
  • Tanimoto M.
Multicenter phase II study of mogamulizumab (KW-0761), a defucosylated anti-cc chemokine receptor 4 antibody, in patients with relapsed peripheral T-cell lymphoma and cutaneous T-cell lymphoma.

 

].

Though promising treatment response, adverse events (AE) are also documented. Among them, infusion reactions and skin rashes are most commonly reported, including Steven-Johnson syndrome [

9

  • Ishida T.
  • Joh T.
  • Uike N.
  • Yamamoto K.
  • Utsunomiya A.
  • Yoshida S.
  • Saburi Y.
  • Miyamoto T.
  • Takemoto S.
  • Suzushima H.
  • Tsukasaki K.
Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: a multicenter phase II study.

 

,

10

  • Ogura M.
  • Ishida T.
  • Hatake K.
  • Taniwaki M.
  • Ando K.
  • Tobinai K.
  • Fujimoto K.
  • Yamamoto K.
  • Miyamoto T.
  • Uike N.
  • Tanimoto M.
Multicenter phase II study of mogamulizumab (KW-0761), a defucosylated anti-cc chemokine receptor 4 antibody, in patients with relapsed peripheral T-cell lymphoma and cutaneous T-cell lymphoma.

 

,

11

  • Ishida T.
  • Jo T.
  • Takemoto S.
  • Suzushima H.
  • Uozumi K.
  • Yamamoto K.
  • Uike N.
  • Saburi Y.
  • Nosaka K.
  • Utsunomiya A.
  • Tobinai K.
Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T‐cell leukaemia‐lymphoma: a randomized phase II study.

 

]. With post-marketing utilization of this novel medication, some studies and case reports have shown an increased risk of hepatitis B reactivation, and cytomegalovirus (CMV) related infection [

11

  • Ishida T.
  • Jo T.
  • Takemoto S.
  • Suzushima H.
  • Uozumi K.
  • Yamamoto K.
  • Uike N.
  • Saburi Y.
  • Nosaka K.
  • Utsunomiya A.
  • Tobinai K.
Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T‐cell leukaemia‐lymphoma: a randomized phase II study.

 

,

12

  • Ifuku H.
  • Kusumoto S.
  • Tanaka Y.
  • Totani H.
  • Ishida T.
  • Okada M.
  • Murakami S.
  • Mizokami M.
  • Ueda R.
  • Iida S.
Fatal reactivation of hepatitis B virus infection in a patient with adult T‐cell leukemia–lymphoma receiving the anti-CC chemokine receptor 4 antibody mogamulizumab.

 

,

13

  • Ishitsuka K.
  • Yurimoto S.
  • Kawamura K.
  • Tsuji Y.
  • Iwabuchi M.
  • Takahashi T.
  • Tobinai K.
Safety and efficacy of mogamulizumab in patients with adult T-cell leukemia–lymphoma in Japan: interim results of post-marketing all-case surveillance.

 

,

14

  • Ishii Y.
  • Itabashi M.
  • Numata A.
  • Yamamoto W.
  • Motohashi K.
  • Hagihara M.
  • Matsumoto K.
  • Fujisawa S.
Cytomegalovirus pneumonia after anti-CC-chemokine receptor 4 monoclonal antibody (mogamulizumab) therapy in an angioimmunoblastic T-cell lymphoma patient.

 

]. However, studies are limited to case reports and series, while no study used large population-based database. Therefore, by a query of Food and Drug Administration adverse events reporting system (FAERS), we aim to investigate the possible relationship between hepatitis B reactivation and CMV related infection and Moga use.

2. Methods

The FAERS database is a voluntary drug and product reporting system that contains data submitted by health care professionals, manufacturers, and consumers [,

16

  • Kessler D.A.
  • Natanblut S.
  • Kennedy D.
  • Lazar E.
  • Rheinstein P.
  • Anello C.
  • Barash D.
  • Bernstein I.
  • Bolger R.
  • Cook K.
  • Couig M.P.
Introducing MEDWatch: a new approach to reporting medication and device adverse effects and product problems.

 

]. AE was coded according to the Medical Dictionary for Regulatory Activities (MedDRA) []. This spontaneous reporting system, containing both reports from the United States (US) and other countries, has received more than 17 million reports since 1968. FARES, functioning as one of the FDA’s post-marketing surveillance tools receives AE, and medical error report continuously and globally. It is a robust method for signal mining. Our study inquired data from FAERS public dashboard between January 1, 2011, and December 31, 2019. AE data for patients who received Moga during the period above were obtained using “Mogamulizumab” and “Mogamulizumab Kpkc.” We then queried the hepatitis B reactivation and CMV related infection in this population using “Hepatitis B Reactivation”, and “Cytomegalovirus Viraemia”, “Cytomegalovirus Infection”, “Cytomegalovirus Chorioretinitis”, “Cytomegalovirus Enteritis”, “Cytomegalovirus Enterocolitis”, “Pneumonia Cytomegaloviral”, “Cytomegalovirus Colitis”, “Cytomegalovirus Duodenitis”, “Cytomegalovirus Gastritis”, “Cytomegalovirus Gastrointestinal Infection”, “Cytomegalovirus Gastrointestinal Ulcer”, “Cytomegalovirus Gastroenteritis”, “Cytomegalovirus Hepatitis”, “Cytomegalovirus Mononucleosis”, “Cytomegalovirus Mucocutaneous Ulcer”, “Cytomegalovirus myocarditis”, “Cytomegalovirus Myelomeningoradiculitis”, “Cytomegalovirus Nephritis”, “Cytomegalovirus Syndrome”, “Cytomegalovirus Oesophagitis”, “Cytomegalovirus Pancreatitis”, “Cytomegalovirus Test Positive”, “Cytomegalovirus Urinary Tract Infection”, “Encephalitis Cytomegalovirus” and “Disseminated Cytomegalovirus Infection”. Then all hepatitis B reactivation and CMV related infection reported in other drugs and biological products were compared to those related to Moga use. The same comparisons were made with rituximab using “Rituximab” and “Rituximab-Abbs,” as well as alemtuzumab using “Alemtuzumab”. Cases were compiled into Microsoft Excel 2016. Variables including suspect product names, the reason for use, reactions, outcomes, sex, event date, patient age, reporter type, concomitant product names, the country where events occurred were collected and analyzed. The reporting odds ratio (ROR) was calculated by SPSS 26 for disproportionality signal GFN (Table 1). The lower limit of two-sided 95% confidence interval (CI) of ROR >1 is considered significant [

18

Quantitative signal detection using spontaneous ADR reporting.

 

,

19

  • Van Puijenbroek E.P.
  • Van Grootheest K.
  • Diemont W.L.
  • Leufkens H.G.
  • Egberts A.C.
Determinants of signal selection in a spontaneous reporting system for adverse drug reactions.

 

].

Table 1Reporting odds ratio of drug of interest.

AE: Adverse Events

ROR=A/CB/D=AXDBXC

95%CI=eln(ROR)±1.961A+1B+1C+1D

Our study adheres to the Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER). The GATHER checklist is attached.No institutional review board or ethics review laws required in our study.

Role of the funding source

No funding in our study.

3. Result

There were in total 13,574,208 reports between January 1, 2011, and December 31, 2019. Among them, 338 (0.00249%) individual cases were related to Moga. Indication for use was reported in only 261 cases, with 159 (47.04%) for CTCL and 102 (30.18%) for ATL. Country of AE origin was reported in 334 cases (98.82%), where 133 (39.35%) were from Asia, 150 (44.37%) from the United States, and 51 (15.09%) from Europe. In the Moga exposure group, five deaths occurred in patients with hepatitis B reactivation, and nine deaths in CMV related infection cases. (Table 2)

Table 2Characteristics of Patients with Hepatitis B Reactivation and CMV Related Infections Post Moga.

Moga=Mogamulizumab; CMV=Cytomegalovirus.

Eight cases were reported for hepatitis B reactivation with Moga use, compared to 2290 cases by using other medications (Table 3). The ROR is 143.67 (p

Table 3Hepatitis B Reactivation in Moga and Other Medications, 2011–2019.

Moga=Mogamulizumab, ROR=Reporting Odds Ratio; CI=Confidence Interval.

CMV related infections were noted in 17 cases using Moga. CMV infection presented as CMV viremia or infection in seven (41.18%) cases, and CMV end-organ disease, including CMV pneumonia in seven (41.18%) cases, CMV enteritis or enterocolitis in two (11.76%) cases, and CMV chorioretinitis in one (5.88%) case, compared with 12,849 cases of CMV related infection using other medications (Tables 4 and 5). The ROR is 55.89 (pp = 0.079). Seven (41.18%) cases had only CMV related infection, while four (23.53%) and six (35.29%) cases reportedly had 1 and 2 or more concomitant other reactions, respectively. The most common concomitant AE are skin rash or erythema in five patients (29.41%), neutropenia in four (23.53%), anemia in two (11.76%), thrombocytopenia in two (11.76%), hypoalbuminemia in two (11.76%), interstitial lung disease in two (11.76%). Heart failure, lymphopenia, infusion-related reaction, transaminitis, cystitis, sepsis, herpes zoster infection, fungal infection, systemic candida, mycotic endophthalmitis, disseminated intravascular coagulation (DIC), hypertriglyceridemia, hypothyroidism, hyperglycemia and weight gain each has been reported once (5.88%)(Table 6).

Table 4CMV Related Infection Post Moga.

Table 5CMV Related infection in Moga and other medications, 2011–2019.

Moga=Mogamulizumab, ROR=Reporting Odds Ratio; CI=Confidence Interval.

Table 6Other adverse events in patients with CMV related infections post Moga.

In comparison, a total of 69,096 AE reported by rituximab and 9662 AE cases by alemtuzumab from 2011 to 2019. For rituximab, 568 cases reported hepatitis B reactivation, with ROR 64.70 (ppppTable 7)

Table 7Comparison of Hepatitis B Reactivation and CMV Infection in Moga,Rituximab and Alemtuzumab,2011–2019.

Moga=Mogamulizumab; ROR=Reporting Odds Ratio; CI=Confidence Interval.

4. Discussion

ATL, caused by human T-cell lymphotropic virus type 1 (HTLV-1), is an aggressive peripheral T cell lymphoma with poor prognosis[

1

Diagnostic criteria and classification of clinical subtypes of adult T-cell leukaemia-lymphoma. A report from the Lymphoma Study Group (1984–87).

 

]. Moga has shown to be an effective and safe medication as monotherapy or in combination with chemotherapy in relapsed/refractory ATL. Moga aims at CCR-4 chemokine receptor, which is expressed on most ATL cells [

21

  • Ishida T.
  • Utsunomiya A.
  • Iida S.
  • Inagaki H.
  • Takatsuka Y.
  • Kusumoto S.
  • Takeuchi G.
  • Shimizu S.
  • Ito M.
  • Komatsu H.
  • Wakita A.
Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma: its close association with skin involvement and unfavorable outcome.

 

]. By binding to CCR-4, Moga enhances antibody-dependent cellular cytotoxicity (ADCC) effect and depletes targeted cells [

21

  • Ishida T.
  • Utsunomiya A.
  • Iida S.
  • Inagaki H.
  • Takatsuka Y.
  • Kusumoto S.
  • Takeuchi G.
  • Shimizu S.
  • Ito M.
  • Komatsu H.
  • Wakita A.
Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma: its close association with skin involvement and unfavorable outcome.

 

]. Moga was later proved to be effective in treating CTCL, which is a heterogeneous group of extranodal non-Hodgkin’s lymphomas. The major types in CTCL are mycosis fungoides (MF), Sézary syndrome (SS), and primary cutaneous peripheral T cell lymphomas not otherwise specified (PCTCL – NOS). Besides advancement in the treatment of ATL and CTCL, some clinical trials evaluating the effectiveness of Moga for other diseases, including solid tumors and HTLV-1 associated myelopathy, have completed []. Doi et al. evaluated Moga in combination with nivolumab in treating advanced or metastatic solid tumors, and 12% ORR was observed in six tumor subtypes with the highest one seen in hepatocellular carcinoma cohort (27%; 95% CI, 8–55) [

24

  • Doi T.
  • Muro K.
  • Ishii H.
  • Kato T.
  • Tsushima T.
  • Takenoyama M.
  • Oizumi S.
  • Gemmoto K.
  • Suna H.
  • Enokitani K.
  • Kawakami T.
A Phase I Study of the Anti-CC Chemokine Receptor 4 Antibody, Mogamulizumab, in Combination with Nivolumab in Patients with Advanced or Metastatic Solid Tumors.

 

]. In a phase 1–2a clinical trial in HTLV-1 associated myelopathy, Moga has shown to decrease the HTLV-1 infected cells and level of inflammatory markers [

25

  • Sato T.
  • Coler-Reilly A.L.
  • Yagishita N.
  • Araya N.
  • Inoue E.
  • Furuta R.
  • Watanabe T.
  • Uchimaru K.
  • Matsuoka M.
  • Matsumoto N.
  • Hasegawa Y.
Mogamulizumab (Anti-CCR4) in HTLV-1–associated myelopathy.

 

].

Since Moga approval, accumulating evidence indicates increased infection risk, including hepatitis B reactivation, CMV, bacteremia, herpes zoster, and mycobacterium infection [

6

  • Yamamoto K.
  • Utsunomiya A.
  • Tobinai K.
  • Tsukasaki K.
  • Uike N.
  • Uozumi K.
  • Yamaguchi K.
  • Yamada Y.
  • Hanada S.
  • Tamura K.
  • Nakamura S.
Phase I study of KW-0761, a defucosylated humanized anti-CCR4 antibody, in relapsed patients with adult T-cell leukemia-lymphoma and peripheral T-cell lymphoma.

 

,

11

  • Ishida T.
  • Jo T.
  • Takemoto S.
  • Suzushima H.
  • Uozumi K.
  • Yamamoto K.
  • Uike N.
  • Saburi Y.
  • Nosaka K.
  • Utsunomiya A.
  • Tobinai K.
Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T‐cell leukaemia‐lymphoma: a randomized phase II study.

 

,

12

  • Ifuku H.
  • Kusumoto S.
  • Tanaka Y.
  • Totani H.
  • Ishida T.
  • Okada M.
  • Murakami S.
  • Mizokami M.
  • Ueda R.
  • Iida S.
Fatal reactivation of hepatitis B virus infection in a patient with adult T‐cell leukemia–lymphoma receiving the anti-CC chemokine receptor 4 antibody mogamulizumab.

 

,

13

  • Ishitsuka K.
  • Yurimoto S.
  • Kawamura K.
  • Tsuji Y.
  • Iwabuchi M.
  • Takahashi T.
  • Tobinai K.
Safety and efficacy of mogamulizumab in patients with adult T-cell leukemia–lymphoma in Japan: interim results of post-marketing all-case surveillance.

 

,

14

  • Ishii Y.
  • Itabashi M.
  • Numata A.
  • Yamamoto W.
  • Motohashi K.
  • Hagihara M.
  • Matsumoto K.
  • Fujisawa S.
Cytomegalovirus pneumonia after anti-CC-chemokine receptor 4 monoclonal antibody (mogamulizumab) therapy in an angioimmunoblastic T-cell lymphoma patient.

 

,

20

  • van der Wekken L.
  • Herbrink J.
  • Snijders D.
  • Chamuleau M.
  • Griffioen A.
Disseminated Mycobacterium chelonae infection in a patient with T-cell lymphoma.

 

,

26

  • Totani H.
  • Kusumoto S.
  • Ishida T.
  • Masuda A.
  • Yoshida T.
  • Ito A.
  • et al.
Reactivation of hepatitis B virus (HBV) infection in adult T-cell leukemia-lymphoma patients with resolved HBV infection following systemic chemotherapy.

 

,

27

  • Nakano N.
  • Kusumoto S.
  • Tanaka Y.
  • Ishida T.
  • Takeuchi S.
  • Takatsuka Y.
  • et al.
Reactivation of hepatitis B virus in a patient with adult T-cell leukemia-lymphoma receiving the anti-CC chemokine receptor 4 antibody mogamulizumab.

 

]. To our knowledge, no previous study using an extensive population-based database has investigated the relationship between these two infections and Moga use. Our study result identified the signal between Moga use and a possible increased risk of developing hepatitis B reactivation and CMV related infection.

In order to investigate the relationship between Moga exposure and the above AEs, we applied disproportionality GFN using ROR. In the process of signal detection, disproportionately high AE rates in a drug of interest comparing to background frequency may indicate a signal [

18

Quantitative signal detection using spontaneous ADR reporting.

 

,

19

  • Van Puijenbroek E.P.
  • Van Grootheest K.
  • Diemont W.L.
  • Leufkens H.G.
  • Egberts A.C.
Determinants of signal selection in a spontaneous reporting system for adverse drug reactions.

 

]. ROR is one of the methods for disproportionality GFN. In our study, it means the odds of reporting hepatitis B reactivation and CMV related infection with Moga use is 143.67 times and 55.89 times of reporting the AE with other medications use, respectively. This disproportionately high frequencies also referred to as “unexpectedness”, representing possibly important signal between Moga use and the increased infectious risks [

18

Quantitative signal detection using spontaneous ADR reporting.

 

].

Hepatitis B reactivation risk has known to increase in patients receiving rituximab, a CD20 antibody, for B cell lymphoma [

34

  • Aksoy S.
  • Harputluoglu H.
  • Kilickap S.
  • Dede D.S.
  • Dizdar O.
  • Altundag K.
  • Barista I.
Rituximab-related viral infections in lymphoma patients.

 

]. In the setting of immunosuppressive conditions, hepatitis B reactivation may attribute to complications from acute hepatitis to fatal fulminant hepatitis [

35

  • Oketani M.
  • Ido A.
  • Uto H.
  • Tsubouchi H.
Prevention of hepatitis B virus reactivation in patients receiving immunosuppressive therapy or chemotherapy.

 

]. However, antiviral treatment after hepatitis onset may not be sufficient to control the infection [

35

  • Oketani M.
  • Ido A.
  • Uto H.
  • Tsubouchi H.
Prevention of hepatitis B virus reactivation in patients receiving immunosuppressive therapy or chemotherapy.

 

]. There are some reports of hepatitis B reactivation in ATL patients with Moga use, including pre-treatment HbsAg negative patients [

12

  • Ifuku H.
  • Kusumoto S.
  • Tanaka Y.
  • Totani H.
  • Ishida T.
  • Okada M.
  • Murakami S.
  • Mizokami M.
  • Ueda R.
  • Iida S.
Fatal reactivation of hepatitis B virus infection in a patient with adult T‐cell leukemia–lymphoma receiving the anti-CC chemokine receptor 4 antibody mogamulizumab.

 

,

13

  • Ishitsuka K.
  • Yurimoto S.
  • Kawamura K.
  • Tsuji Y.
  • Iwabuchi M.
  • Takahashi T.
  • Tobinai K.
Safety and efficacy of mogamulizumab in patients with adult T-cell leukemia–lymphoma in Japan: interim results of post-marketing all-case surveillance.

 

,

26

  • Totani H.
  • Kusumoto S.
  • Ishida T.
  • Masuda A.
  • Yoshida T.
  • Ito A.
  • et al.
Reactivation of hepatitis B virus (HBV) infection in adult T-cell leukemia-lymphoma patients with resolved HBV infection following systemic chemotherapy.

 

,

27

  • Nakano N.
  • Kusumoto S.
  • Tanaka Y.
  • Ishida T.
  • Takeuchi S.
  • Takatsuka Y.
  • et al.
Reactivation of hepatitis B virus in a patient with adult T-cell leukemia-lymphoma receiving the anti-CC chemokine receptor 4 antibody mogamulizumab.

 

]. Similarly, CMV related infection and end-organ failure contribute to increased morbidity and mortality in patients receiving hematopoietic stem cell transplant (HSCT) [

30

  • Boeckh M.
  • Nichols W.G.
  • Papanicolaou G.
  • Rubin R.
  • Wingard J.R.
  • Zaia J.
Cytomegalovirus in hematopoietic stem cell transplant recipients: current status, known challenges, and future strategies.

 

]. CMV infection has also been reported in patients undergoing chemotherapy for lymphoma [

32

  • Torres H.A.
  • Kontoyiannis D.P.
  • Aguilera E.A.
  • Younes A.
  • Luna M.A.
  • Tarrand J.J.
  • Nogueras G.M.
  • Raad I.I.
  • Chemaly R.F.
Cytomegalovirus infection in patients with lymphoma: an important cause of morbidity and mortality.

 

], and is a well-known infectious complication related to alemtuzumab and rituximab use [

33

  • Lundin J.
  • Hagberg H.
  • Repp R.
  • Cavallin-Ståhl E.
  • Fredén S.
  • Juliusson G.
  • Rosenblad E.
  • Tjønnfjord G.
  • Wiklund T.
  • Österborg A.
Phase 2 study of alemtuzumab (anti-CD52 monoclonal antibody) in patients with advanced mycosis fungoides/Sezary syndrome.

 

,

34

  • Aksoy S.
  • Harputluoglu H.
  • Kilickap S.
  • Dede D.S.
  • Dizdar O.
  • Altundag K.
  • Barista I.
Rituximab-related viral infections in lymphoma patients.

 

]. Recent studies, including clinical trials, have also shown more CMV related infection in patients receiving Moga, especially in combination with chemotherapy [

11

  • Ishida T.
  • Jo T.
  • Takemoto S.
  • Suzushima H.
  • Uozumi K.
  • Yamamoto K.
  • Uike N.
  • Saburi Y.
  • Nosaka K.
  • Utsunomiya A.
  • Tobinai K.
Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T‐cell leukaemia‐lymphoma: a randomized phase II study.

 

,

13

  • Ishitsuka K.
  • Yurimoto S.
  • Kawamura K.
  • Tsuji Y.
  • Iwabuchi M.
  • Takahashi T.
  • Tobinai K.
Safety and efficacy of mogamulizumab in patients with adult T-cell leukemia–lymphoma in Japan: interim results of post-marketing all-case surveillance.

 

]. Our study compared reported hepatitis B reactivation and CMV related infection in patients using rituximab and alemtuzumab to Moga during the same period. Surprisingly, ROR with Moga is higher in both infections than rituximab and alemtuzumab. Admittedly, being in the market for longer time, clinical practitioners are more familiar with infectious AE of rituximab and alemtuzumab’s. This knowledge results in less voluntary reporting and can lower the contribution of reported infectious AE to all AE. Increased ROR is a signal that Moga use may increase both infection risk.

The mechanism for observed increased risk with Moga use is not well established. Host cells with CCR-4 receptors, like Th2 cells, some CD4+ memory cells, and Tregs [

21

  • Ishida T.
  • Utsunomiya A.
  • Iida S.
  • Inagaki H.
  • Takatsuka Y.
  • Kusumoto S.
  • Takeuchi G.
  • Shimizu S.
  • Ito M.
  • Komatsu H.
  • Wakita A.
Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma: its close association with skin involvement and unfavorable outcome.

 

,

22

  • Imai T.
  • Nagira M.
  • Takagi S.
  • Kakizaki M.
  • Nishimura M.
  • Wang J.
  • Gray P.W.
  • Matsushima K.
  • Yoshie O.
Selective recruitment of CCR4-bearing Th2 cells toward antigen-presenting cells by the CC chemokines thymus and activation-regulated chemokine and macrophage-derived chemokine.

 

], are all targeted by Moga. With the combined effect of lymphopenia, cellular and innate immune cells depletion, and the immunosuppressive nature of T-cell malignancy itself, infectious AE, including hepatitis B reactivation and CMV related infection, are expected. Also, immunologic exacerbation to infection may play a role in end-organ failure under the hypothesis of Treg cell impairment [

29

  • Reinwald M.
  • Silva J.T.
  • Mueller N.J.
  • Fortún J.
  • Garzoni C.
  • de Fijter J.W.
  • Fernández-Ruiz M.
  • Grossi P.
  • Aguado J.M.
ESCMID study group for infections in compromised hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Intracellular signaling pathways: tyrosine kinase and mTOR inhibitors).

 

].

Our study showed that 10 (58.82%) out of 17 patients with CMV related infection developed CMV end-organ diseases. Nine CMV related infection patients died, of whom six deaths (66.67%) occurred in patients with CMV end-organ disease. This ratio is higher than other reports: Tay et al. studied CMV infection and end-organ disease in Asian patients with lymphoma receiving chemotherapy, and 12 (25.00%) of 48 patients with CMV infection developed CMV end-organ disease [

31

  • Tay M.R.J.
  • Lim S.T.
  • Tao M.
  • Quek R.H.H.
  • Tay K.
  • Tan T.T.
Cytomegalovirus infection and end-organ disease in Asian patients with lymphoma receiving chemotherapy.

 

]. The higher number of deaths in CMV end-organ disease in our study could be related to the under-reporting of CMV viremia patients in FAERS.

Furthermore, 10 (58.82%) of them have other AE reported in addition to CMV related infection. This is different from reports for hepatitis B reactivation, where all eight patients have no other AE documented. Seven (87.50%) of the eight patients with hepatitis B reactivation have concomitant chemotherapy use, some including steroids. Further studies are warranted to assess the impact of Moga alone and with chemotherapy on the increased risk of hepatitis B reactivation and CMV infection.

Many studies have evaluated the efficiency of preventive measures on patients with positive HBsAg [

35

  • Oketani M.
  • Ido A.
  • Uto H.
  • Tsubouchi H.
Prevention of hepatitis B virus reactivation in patients receiving immunosuppressive therapy or chemotherapy.

 

,

36

  • Loomba R.
  • Rowley A.
  • Wesley R.
  • Liang T.J.
  • Hoofnagle J.H.
  • Pucino F.
  • Csako G.
Systematic review: the effect of preventive lamivudine on hepatitis B reactivation during chemotherapy.

 

]. For previously resolved hepatitis B (HBsAg negative), high-risk patients, including anti-HBc positive subjects to be treated with rituximab or those undergoing stem cell transplantation, antiviral prophylaxis is recommended [

37

EASL clinical practice guidelines
Management of chronic hepatitis B virus infection.

 

]. Pre-emptive therapy by monitoring hepatitis B deoxyribonucleic aicd (DNA) has been recommended for moderate-risk patients in some guidelines [

37

EASL clinical practice guidelines
Management of chronic hepatitis B virus infection.

 

]. In one study, a monthly hepatitis B DNA monitoring has shown to be useful in early detection of hepatitis B reactivation of previously resolved hepatitis B infection in patients receiving rituximab and steroid containing chemotherapy [

38

  • Hsu C.
  • Tsou H.H.
  • Lin S.J.
  • Wang M.C.
  • Yao M.
  • Hwang W.L.
  • Kao W.Y.
  • Chiu C.F.
  • Lin S.F.
  • Lin J.
  • Chang C.S.
Chemotherapy induced hepatitis B reactivation in lymphoma patients with resolved HBV infection: a prospective study.

 

]. Pre-emptive screening of CMV for patients using alemtuzumab has been described in some guidelines [

28

  • Sandherr M.
  • Einsele H.
  • Hebart H.
  • et al.
Antiviral prophylaxis in patients with haematological malignancies and solid tumours: guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society for Hematology and Oncology (DGHO).

 

]. Our result demonstrated a potential higher risk of infection with Moga use, and pre-emptive screening and risk GFN should be considered in clinical practice.

Our study has some limitations. First, we used FAERS, a voluntary reporting system database without strict research protocol, randomization, and control, for signal mining. The relationship between a specific drug and AE of interest is hard to be determined based only on the database, and causation relationship not necessarily exist even if significant disproportionality GFN result. Also, there is a possibility of duplicate reports when the consumer, and the sponsor submits the same case, and the data may change due to the correction for duplication. Though this change may not be significant in the long term, and FAERS provided quarterly extract files for all previous data. Besides, missing and incomplete information, including dosage, pre-treatment infection condition, patient baseline characteristics, and follow up data, may create bias when analyzing these data. For instance, pre-treatment hepatitis B serostatus is not available from the FAERS, which can lead to selection bias when discussing the risk of hepatitis B reactivation post-Moga exposure.

Second, even though more AE reports have been noticed than previous studies [

9

  • Ishida T.
  • Joh T.
  • Uike N.
  • Yamamoto K.
  • Utsunomiya A.
  • Yoshida S.
  • Saburi Y.
  • Miyamoto T.
  • Takemoto S.
  • Suzushima H.
  • Tsukasaki K.
Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: a multicenter phase II study.

 

14

  • Ishii Y.
  • Itabashi M.
  • Numata A.
  • Yamamoto W.
  • Motohashi K.
  • Hagihara M.
  • Matsumoto K.
  • Fujisawa S.
Cytomegalovirus pneumonia after anti-CC-chemokine receptor 4 monoclonal antibody (mogamulizumab) therapy in an angioimmunoblastic T-cell lymphoma patient.

 

], the total number of reported hepatitis B reactivation and CMV related infections in this study is still low, given the limited period and nature of spontaneous reporting database.

Using FARES, we identified a positive signal between Moga exposure and hepatitis B reactivation as well as CMV related infection. A consideration in future studies should be placed on confirming the relationship and investigating need for pre-treatment screening, close monitoring, and utilization of prophylaxis in this populationbased on pre-treatment risks.

Declaration of Competing Interest

Dr. Abhishek Kumar declared the following interest: Stocks in Abbvie Inc, Acadia Pharmaceuticals, ADMA Biologics, Agneus Inc, Aikido Pharma Inc, Albireo Pharma Inc, Amgen Inc, Aveo Pharma, Astrazeneca PLC, Bristol Meyer Squibb, Biopath Holdings, BeyondSpring Inc, Blueprint Medicine, Cara Therapeutics, Chembio Diagnostics, contrafect Corp, Cardiff Oncology, CRISPR Therapeutics, CVS Health Corporation, Precision Biosciences, Editas Medicine Inc, Five Prime Therapeutics, Globus Medical Inc, IDEXX Laboratories, Immunomedics Inc, IOvance Biosciences, Johnson & Johnson, Eli Lilly and Co, Novavax Inc, Northwest Biotherapeutics, Pfizer, Poseida Therapeutics, PTC Therapeutics, Spectrum Therapeutics, Surgalign Holdings, Viking therapeutics, and, Vertex Pharmaceuticals. The other authors declared no conflicts of interest.

Election

Why 780 retired generals and former national security leaders spoke out against Trump

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Donald Trump
Trump departs the White House for a photo op outside St. John’s Church on June 1, 2020. Walking behind the president are, from left, Attorney General William Barr, Secretary of Defense Mark Esper and Gen. Mark Milley, chairman of the Joint Chiefs of Staff. (Patrick Semansky/AP)

On June 1, retired Army vice chief of staff Gen. Peter Chiarelli sat staring out at the Pacific Ocean in Gearhart, Ore., where his family had vacationed throughout his long military career. The peaceful scene was occasionally interrupted by the news flashing across the notebook computer in his lap. In a Rose Garden speech that afternoon, President Trump addressed the racial justice protests spreading across the nation after the brutal killing of George Floyd in police custody a week earlier.

In the speech, Trump proclaimed himself “your president of law and order,” and claimed the protests had been hijacked by “professional anarchists, violent mobs, arsonists, looters, criminals, rider rioters, antifa and others” intent on “domestic terror.” News cameras showed some of the hundreds of National Guard troops from around the country that had been sent to reinforce the D.C. Guard, and there were reports that 1,600 active-duty troops were on high alert just outside the capital. Privately, Trump was threatening to invoke the Insurrection Act in order to send thousands more active-duty troops onto the nation’s streets in a show of dominant military force, criticizing weak governors and mayors around the country for not doing more to forcefully stamp out the protests.

The television cameras shifted to a mostly peaceful crowd of protesters across Lafayette Park from the White House. Chiarelli sat up when a phalanx of federal police and National Guard troops suddenly marched into the peaceful crowd, backed by a small cavalry of Park Police on horseback. There were flash-bang explosions, clouds of tear gas and the crackle of pepper balls as riot police used shields and batons to pummel some in the crowd. A woman could be heard plaintively shouting above the din, “Why are you shooting at us?!”

After the crowd was dispersed, Chiarelli watched with growing alarm as President Trump strode purposefully across Lafayette Park flanked by Attorney General William Barr, Defense Secretary Mark Esper, and Gen. Mark Milley, chairman of the Joint Chiefs of Staff. Chiarelli had served in combat with Milley in Iraq, and considered him a good friend. That Mark Milley would have known better than to appear at the president’s side in his camouflage uniform after a show of dominant force against protesters on the streets of America.

In front of historic Saint John’s Church, damaged by fire during earlier protests, Trump posed silently holding a bible aloft for a 2-minute photo op. At long last, President Trump had the image of the “American carnage” that he had promised to end in his inauguration speech, insisting that he alone could fix it.

Donald Trump
President Trump holds a Bible as he visits St. John’s Church across Lafayette Park from the White House on June 1, 2020. (Patrick Semansky/AP)

Along with a cadre of other retired generals, a very upset Peter Chiarelli decided to contact his old friend General Milley, the most senior uniformed leader in the country. After serving as commander of the 147.000 U.S. and coalition troops of Multi-National Corps – Iraq, Chiarelli as vice chief of the Army had led Defense Department efforts to treat post-traumatic stress, traumatic brain injury and suicide prevention. On his retirement in 2012, he became the first CEO of One Mind, which supports research into brain illnesses and injuries.

“That whole incident around Lafayette Square was stunning to me, because those were mostly peaceful demonstrators exercising a right guaranteed by the Constitution that I’ve sworn allegiance to throughout my entire career,” said Chiarelli in an interview. That allegiance is not given to a political party, Congress or the president of the United States, he noted, making the image of a uniformed chairman of the Joint Chiefs and the defense secretary at Trump’s side that day so alarming. General Milley later apologized for his presence in Lafayette Square, and Defense Secretary Mark Esper earned the president’s enmity by publicly opposing invocation of the Insurrection Act in order to use U.S. military troops to “dominate” the streets.

Along with more than 780 retired high-ranking officers and former national security leaders — including 22 retired four-star generals and admirals and five former secretaries of defense — Chiarelli signed an “Open Letter to America” endorsing Joe Biden for president. “We love our country,” the signatories wrote. “Unfortunately, we also fear for it.”

“Signing that letter was very hard for me to do, because I have never done that before or even given a dollar to a political campaign. Frankly, even as a retired general I didn’t think it was the right thing to do,” said Chiarelli, stressing that active-duty military officers are indoctrinated from a young age to remain strictly nonpartisan and apolitical. “But this president has assaulted the military justice system on behalf of individuals charged with war crimes. He has ended the career of service members like [impeachment witness Lt. Col. Alexander] Vindman for doing his duty and what was right. He has maligned mail-in voting as a fraud and suggested he might claim victory in a close election before all the ballots are counted, when as a service member I have voted absentee by mail my entire life. So like everyone else I’ve become numb after four years of this, but we have gone places in that time that I never dreamt we would go as a nation. I really do fear that the republic that I swore allegiance to is now under threat.”

Peter Chiarelli
Retired Gen. Peter Chiarelli. (Alastair Grant/AP)

Even among the cascade of scandals and controversies that have characterized the Trump presidency, the use of excessive force against mostly peaceful protesters near Lafayette Square, and the involvement of the top ranks of  the U.S. military, still stands out. The incident conjured a truly dystopian vision of a U.S. president not only willing but eager to use the world’s most powerful military to crush domestic protests and “dominate” the streets of America, one that an increasing number of retired generals and senior national security experts believe could become all too real in a second Trump term.

Lafayette Square was so alarming that it shook Trump’s former Defense Secretary, retired four-star Marine Gen. Jim Mattis, out of his long silence on the president’s leadership, writing afterwards that “Donald Trump is the first president in my lifetime who does not try to unite the American people — does not even pretend to try.”

Trump’s troubling authoritarian instincts, focus on image over substance, constant misuse and politicization of nonpartisan institutions and penchant for chaos were all on clear display in Lafayette Square, and the incident crystalized the concerns expressed in the open letter. Traditionally both active-duty and retired U.S. military and intelligence officials have steered clear of politics, but in mid-September the Trump campaign released a letter signed by 235 retired senior military officers endorsing the president for reelection with the claim that Americans’ “historic way of life is at stake” if the “socialists and Marxists” of the Democratic Party take control of the government.

The willingness of hundreds of career officers to break with tradition and speak out on behalf of one candidate reflects beliefs, on both sides, that the nation faces an uncertain future, facing the worst pandemic in over a century, the worst economic decline since the Great Depression and the worst racial unrest since the 1960s. To the signers of the “Open Letter to America,” a second Trump term would only make things worse.

Protestors
Protestors at Lafayette Park on June 1, 2020. (Ken Cedeno/Reuters)

“Over the last three-plus years, I’ve watched the Trump administration politicize the Department of Justice and eviscerate the State Department, and the situation in Lafayette Square made clear that if reelected, Trump will politicize the Defense Department as well,” said retired Rear Adm. Mike Smith, who was instrumental in organizing the “Open Letter to America.” “A lot of us who spent our careers in the military would rather have stayed out of politics, but we have a deep moral conviction that the country can’t afford to go through another four years of this kind of leadership.”

Already the Lafayette Square incident has sunk beneath a wave of subsequent controversies and scandals, including recent revelations in investigative reporter Bob Woodward’s book “Rage,” based on numerous on-the-record interviews with Trump, that the president knew early on about the deadly and extremely contagious nature of the COVID-19 virus, but chose to continually play down the threat; the revelations in an article in the Atlantic, backed by reporting by the Washington Post, Fox News and other outlets, that Trump has repeatedly shown contempt for U.S. service members killed in combat, including referring to fallen soldiers and marines in cemeteries overseas as “losers” and “suckers”; Trump’s bullying and hectoring performance in the first presidential debate that astounded viewers at home and abroad; the president’s decision to put the health and lives of his Secret Service detail in jeopardy for a photo op after he tested positive for the coronavirus; and Trump’s insistence that the presidential election weeks away will be “the most rigged” in history, and his refusal to commit to accepting its results and peacefully transfer power if he loses.

Civil-Military Dysfunction

Donald Trump and Melania Trump
Donald and Melania Trump celebrate Independence Day on the South Lawn of the White House, July 4, 2020. (Carlos Barria/Reuters)

President Trump’s relationship with military commanders might have been an asset in his reelection campaign. He has increased defense spending each year of his presidency, with the United States on track to spend more on the military in 2020 (adjusted for inflation) than at any point since World War II, with the exception of a few years at the height of the Iraq War. Early in his term, Trump pleased commanders by relaxing battlefield restrictions in the fight against the Islamic State of Iraq and Syria (ISIS), and he ordered successful strikes that killed ISIS leader Abu Bakr al-Baghdadi and Iranian Quds Force leader Qassem Soleimani.

As commander in chief, Trump also clearly revels in the pomp and spectacle of military parades, and in salutes to the troops. Yet from the early days of his presidency there were signs of severe tension between a president who has racked up an unprecedented 20,000 falsehoods since taking the oath, according to the Washington Post’s “Fact Checker,” and an institution built on the ethos that officers “will not lie, cheat, steal, or tolerate those who do.” There were also early indications that Trump was willing to politicize the most stringently apolitical institution in the U.S. government, treating appearances with the troops like political rallies where he excoriated Democrats and signed “Make America Great Again” hats. Before the 2018 midterm elections, Trump alarmed senior military leaders by sending active-duty troops to the southern border to confront a ragtag caravan of asylum seekers and migrants in a nakedly political stunt, and he diverted Pentagon funds to build sections of the wall he promised that Mexico would pay for.

From the beginning of his term, Trump has also exhibited indifference bordering on contempt for the sacrifices and principle of selfless service that underlies the military profession. Many officers were willing to look past the five draft deferments Trump received during the Vietnam War, including one for a “bone spur” diagnosis from a New York podiatrist who reportedly rented an apartment from Trump’s father.

More troubling to many uniformed leaders was Trump’s belittling of the Muslim Gold Star parents of a slain U.S. soldier who criticized him during the 2016 Democratic National Convention, and the president’s casual dismissal of the wartime service of the late Sen. John McCain, a former Navy pilot who spent more than five years being tormented in the notorious “Hanoi Hilton” prison. “He’s not a war hero,” said candidate Trump, when he was feuding with the Arizona senator. “He was a war hero because he was captured. I like people who weren’t captured.”

Donald Trump
Then presidential candidate Donald Trump speaks at the Family Leadership Summit in Ames, Iowa, in July 2015. (Nat Harnik/AP)

In his first briefing inside the Pentagon’s classified “tank” with then Defense Secretary Mattis and the Joint Chiefs, Trump famously bristled at their arguments supporting NATO and ongoing operations in Afghanistan. “You’re all losers,” Trump reportedly said to a room full of four-star flag officers and combat veterans. “You don’t know how to win anymore.” After Mattis later resigned to protest Trump’s rash decision to pull U.S. troops out of Syria and abandon Kurdish allies in the fight against ISIS, Trump publicly dissed him as “the world’s most overrated general.”

“President Trump routinely shows disrespect towards exemplary leaders like Senator McCain, and towards General Jim Mattis, one of our very best,” said retired Marine Lt. General Frank Libutti, a combat veteran and Purple Heart recipient who signed the “Open Letter to America.” “It recalls his public ridicule of many of his top military and intelligence community leaders, and his insistence that he knows more about issues of national security than they do, which is nonsense. But what I found truly shocking were Trump’s comments about the Marines who sacrificed their lives for victory at Belleau Wood. I believe words count. Character counts. Temperament counts. And President Trump has shown himself beneath the dignity of the office.”

A seeming contempt for military service came through most clearly when Trump canceled a planned visit to a World War I military cemetery near Paris because of rain during a 2018 trip. Quoting four anonymous sources with firsthand knowledge of the discussion that day, the Atlantic’s editor in chief Jeffrey Goldberg reported that Trump said, “Why should I go to that cemetery? It’s filled with losers.” In a separate conversation on the same trip, Trump reportedly referred to the more than 1,800 Marines who lost their lives at Belleau Wood as “suckers” for getting killed. Fox News and the Washington Post later confirmed similar episodes of the president denigrating military service.

Retired Air Force Gen. Charles Boyd spent more than six years as a prisoner of war in North Vietnam, and he is the only Vietnam War POW to later reach four-star rank. “When I read the Atlantic article, I found it absolutely disgusting. The idea that the commander in chief holds those who serve under him with such contempt, just because they are not driven by the same desire for money and wealth as him, made me sick to my stomach. In all of my experiences in life, I’ve never known any group that is more honorable than military professionals, who sign an unlimited liability contract to sacrifice their lives if called to for this nation.”

In the past, Boyd has also opposed even retired flag officers endorsing candidates or becoming involved in partisan politics, but he made an exception this year by signing the “Open Letter to America.” “There’s a saying in the military that ‘officers eat last,’ which means that leadership is all about what’s best for your troops, and for the nation. President Trump has no concept of that kind of leadership. Everything he does is driven by what’s best for him personally, including casting doubt on any election results that don’t declare him the winner. That’s destructive to the very fiber of our democracy.”

_____

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Twin Cities area youth sports coaches add COVID-19 protocols to daily routines

Emily walpole

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Mary Guzek is used to playing the role of “Team Mom” for her two sons’ Fridley youth football, basketball and baseball squads. Time was, that meant supplying snacks or filling water bottles.

But this fall, in the midst of a global pandemic, it means taking players’ temperatures before every practice and game, counseling parents of sick kids to keep them home and running down a checklist of whether any of the 22 players on the fifth-grade football team have a cough or feel short of breath.

“Unfortunately, it’s what we have had to do to make sure our kids can play,” said Guzek, whose boys are 12 and 10. “But it was worse in the spring, when seasons were canceled, and the kids were sad and depressed. Now, they can play.”

It’s hard enough for some parents to volunteer their time and energy at the end of a workday to coach youth sports. But with COVID-19 rapidly spreading, they’re now forced to do more than manage lineups and the Xs and Os to keep players on the field and the virus at bay.

Many parents and volunteer coaches across the metro have added COVID-19 protocols to their duties. Taking player temperatures, scrubbing down equipment and alternating practice times have, for most, become routine. Meanwhile, some park and recreation departments, not wanting to saddle volunteers with such responsibility, have moved away from traditional soccer and football games, offering instead skills camps run by paid staff members at a handful of hub sites.

Jayme Murphy, who focuses on COVID-19 issues for the Minnesota Amateur Sports Commission, said youth sports groups across the state spent much of the summer exploring ways they could safely play in the fall. Some, he said, were committed to playing out the season. Others created scaled-down versions of their usual offerings. Still others canceled seasons altogether.

Key to those decisions was determining whether coaches and parent volunteers would feel overwhelmed by the responsibility for keeping COVID-19 in check. The Minnesota Department of Health has issued 13 pages of guidelines for safely conducting youth and adult sports.

“The question for volunteers and parents to ask themselves is how comfortable are they with risk?” Murphy said. “If you’re uncomfortable with this, if you’re uncomfortable with your child’s participation in this, that’s ok.”

With COVID-19 cases continuing to rise across the state this fall, those comfort levels may be challenged even more as the winter sports season approaches.

Another way

In St. Paul, officials at the city’s Parks and Recreation department canceled sports at 26 recreation centers over the spring and summer. This fall, they replaced tackle football and competitive soccer with flag football and soccer skills programs hosted at six recreation centers.

They did so, because “we didn’t want to throw the responsibility for following those protocols onto volunteer coaches,” said Andy Rodriguez, recreation services manager.

By limiting offerings to six sites, supervised by city employees with help from coaches at Cretin-Derham Hall and the Sanneh Foundation, Rodriguez said the city can better control social distancing, sanitizing equipment and health screening. Nearly 600 kids, ages 3-14, registered for soccer in St. Paul, Rodriguez said. Almost 400 kids, ages 8-12, signed up for flag football.

“For the most part, the families we have been working with are just thankful for something for their kids to do in the fall,” he said.

Davis Vue who helped his 7-year-old son Memphis tie his shoes on a recent night, said he is one of the happy parents. The St. Paul native watched the coronavirus wipe out his own flag football league season, so he appreciates the city finding a way for Memphis to participate. It’s his son’s first year playing and he hasn’t missed a night, his father said.

“With this pandemic going on, I’m surprised Parks and Rec had this going on for kids,” Vue said. “I’m really glad they did.”

There’s also no tackle football in Minneapolis, where the city’s Park Board has offered flag football for young athletes 6-18. The soccer season has continued with a citywide schedule and volunteer coaches, said Mimi Kalb, director of Athletic Programs and Aquatics for the Minneapolis Park Board. Younger children — on 6U and 8U teams — are playing games in “smaller service areas” with city staff members conducting many of the COVID-19 protocols, she said.

Some coaches and players and families opted out of playing, “but for those who wanted to play, we tried to take a lot of the responsibility off the coaches,” she said. “Our park staff and league directors are doing a lot of that.”

Tim Grate, athletics program director for Minneapolis Parks and Recreation, said many coaches have successfully incorporated their new responsibilities.

“I’ve seen coaches who laid out cones to make sure [players are] social distancing,” he said. “I haven’t heard a lot of complaints.”

John Swanson, a Fridley varsity football coach who oversees more than 200 youth teams across the north metro, said about 30 % of them opted out of play due to COVID-19 concerns. Those that remained were committed to following all the necessary rules to keep playing.

“It’s one of the few things that still connects community,” he said. “Youth sports help us maintain that connectivity.”

Coaches and team moms and dads are keeping spreadsheets, taking temperatures, cleaning equipment, staggering practice nights and holding kids out if they show symptoms or test positive, he said. Teams have built time into their schedules to play makeup games when any had to quarantine for 14 days. So far, he said, there have been no COVID-19 cases transmitted on the football field.

“I don’t think we are asking the coaches to do too much,” Swanson said. “Volunteer coaches have proved they can do it.”

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tsla-ex991_57.pptx.htm

Mish Boyka

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Slide 1

Q3 2020 Update Exhibit 99.1

Slide 2

Highlights 03 Financial Summary04 Operational Summary06 Vehicle Capacity 07 Core Technology 08 Other Highlights09 Outlook10 Battery Day Highlights11 Photos & Charts13 Financial Statements23 Additional Information28

Slide 3

The third quarter of 2020 was a record quarter on many levels. Over the past four quarters, we generated over $1.9B of free cash flow while spending $2.4B on new production capacity, service centers, Supercharging locations and other capital investments.  While we took additional SBC expense in Q3, our GAAP operating margin reached 9.2%. We are increasingly focused on our next phase of growth. Our most recent capacity expansion investments are now stabilizing with Model 3 in Shanghai achieving its designed production rate and Model Y in Fremont expected to reach capacity-level production soon. During this next phase, we are implementing more ambitious architectural changes to our products and factories to improve manufacturing cost and efficiency. We are also expanding our scope of manufacturing to include additional areas of insourcing. At Tesla Battery Day, we announced our plans to manufacture battery cells in-house to aid in our rapid expansion plan. We believe our new 4680 cells are an important step forward to reduce cost and improve capital efficiency, while improving performance. We continue to see growing interest in our cars, storage and solar products and remain focused on cost-efficiency while growing capacity as quickly as possible. $5.9B increase in our cash and cash equivalents in Q3 to $14.5B Operating cash flow less capex (free cash flow) of $1.4B in Q3 Cash Record vehicle deliveries, profitability and free cash flow Buildout of three new factories on three continents continues as planned First step of FSD beta rollout started in Oct. 2020 Profitability $809M GAAP operating income; 9.2% operating margin in Q3 $331M GAAP net income; $874M non-GAAP net income (ex-SBC) in Q3 SBC expense increased to $543M (driven by 2018 CEO award milestones) Operations S U M M A R Y H I G H L I G H T S 3 SBC = stock-based compensation

Slide 4

F I N A N C I A L   S U M M A R Y (Unaudited) 4 ($ in millions, except percentages and per share data) Q3-2019 Q4-2019 Q1-2020 Q2-2020 Q3-2020 QoQ YoY Automotive revenues 5,353 6,368 5,132 5,179 7,611 47% 42%    of which regulatory credits 134 133 354 428 397 -7% 196% Automotive gross profit 1,222 1,434 1,311 1,317 2,105 60% 72% Automotive gross margin 22.8% 22.5% 25.5% 25.4% 27.7% 223 bp 483 bp               Total revenues 6,303 7,384 5,985 6,036 8,771 45% 39% Total gross profit 1,191 1,391 1,234 1,267 2,063 63% 73% Total GAAP gross margin 18.9% 18.8% 20.6% 21.0% 23.5% 253 bp 462 bp               Operating expenses 930 1,032 951 940 1,254 33% 35% Income from operations 261 359 283 327 809 147% 210% Operating margin 4.1% 4.9% 4.7% 5.4% 9.2% 381 bp 508 bp               Adjusted EBITDA 1,083 1,175 951 1,209 1,807 49% 67% Adjusted EBITDA margin 17.2% 15.9% 15.9% 20.0% 20.6% 57 bp 342 bp               Net income attributable to common stockholders (GAAP) 143 105 16 104 331 218% 131% Net income attributable to common stockholders (non-GAAP) 342 386 227 451 874 94% 156%               EPS attributable to common stockholders, diluted (GAAP) (1) 0.16 0.11 0.02 0.10 0.27 170% 69% EPS attributable to common stockholders, diluted (non-GAAP) (1) 0.37 0.41 0.23 0.44 0.76 73% 105%               Net cash provided by (used in) operating activities 756 1,425 (440) 964 2,400 149% 217% Capital expenditures (385) (412) (455) (546) (1,005) 84% 161% Free cash flow 371 1,013 (895) 418 1,395 234% 276% Cash and cash equivalents 5,338 6,268 8,080 8,615 14,531 69% 172% (1) Prior period results have been retroactively adjusted to reflect the five-for-one stock split effected in the form of a stock dividend in August 2020. EPS = Earnings per share

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F I N A N C I A L   S U M M A R Y Revenue Profitability Cash Total revenue grew 39% YoY in Q3. This was achieved mainly through substantial growth in vehicle deliveries as well as growth in other parts of the business. At the same time, vehicle average selling price (ASP) declined slightly compared to the same period last year as our product mix continues to shift from Model S and Model X to the more affordable Model 3 and Model Y. Our operating income improved in Q3 to a record level of $809M, resulting in a 9.2% operating margin. This profit level was reached while we took increased SBC expense in Q3 attributable to the 2018 CEO award, of which $290M was triggered by a significant increase in share price and market capitalization and a new operational milestone becoming probable. Positive profit impacts included strong volume, better fixed cost absorption and continuous cost reduction.  Quarter-end cash and cash equivalents increased by $5.9B QoQ to $14.5B, driven mainly by our recent capital raise of $5.0B (average price of this offering was ~$449/share) combined with free cash flow of $1.4B and partially offset by reduced use of working capital credit lines. Since our days payable outstanding (DPO) are higher than days sales outstanding (DSO), revenue growth results in additional cash generation from working capital. DPO and DSO both declined sequentially in Q3 2020.  5

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Q3-2019 Q4-2019 Q1-2020 Q2-2020 Q3-2020 QoQ YoY Model S/X production 16,318 17,933 15,390 6,326 16,992 169% 4% Model 3/Y production 79,837 86,958 87,282 75,946 128,044 69% 60% Total production 96,155 104,891 102,672 82,272 145,036 76% 51% Model S/X deliveries 17,483 19,475 12,230 10,614 15,275 44% -13% Model 3/Y deliveries 79,703 92,620 76,266 80,277 124,318 55% 56% Total deliveries 97,186 112,095 88,496 90,891 139,593 54% 44%    of which subject to operating lease accounting 9,086 8,848 6,104 4,716 10,014 112% 10% Total end of quarter operating lease vehicle count 44,241 49,901 53,159 54,519 61,638 13% 39% Global vehicle inventory (days of supply)(1) 18 10 25 17 14 -18% -22% Solar deployed (MW) 43 54 35 27 57 111% 33% Storage deployed (MWh) 477 530 260 419 759 81% 59% Store and service locations 417 433 438 446 466 4% 12% Mobile service fleet 719 743 756 769 780 1% 8% Supercharger stations 1,653 1,821 1,917 2,035 2,181 7% 32% Supercharger connectors 14,658 16,104 17,007 18,100 19,437 7% 33% (1) Days of supply is calculated by dividing new car ending inventory by the quarter’s deliveries and using 75 trading days (aligned with Automotive News definition). 6 O P E R A T I O N A L   S U M M A R Y (Unaudited)

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Delivery percentage of locally-made vehicles* V E H I C L E C A P A C I T Y Fremont We have recently increased capacity of Model 3 / Model Y to 500,000 units a year. In order to do this, we restarted our second paint shop, installed the largest die-casting machine in the world and upgraded our Model Y general assembly line. Production should reach full capacity toward the end of this year or beginning of next year. Shanghai Model 3 production capacity has increased to 250,000 units a year. We reduced the price of Model 3 to 249,900 RMB after incentives, making it the lowest-price premium mid-sized sedan1 in China. This was enabled both by lower-cost batteries and an increased level of local procurement. As a result of this shift in cost and starting price, we recently added a third production shift to our Model 3 factory. Berlin-Brandenburg Construction of the Gigafactory in Berlin continues to progress rapidly. Buildings are under construction and equipment move-in will start over the coming weeks. At the same time, the Giga Berlin team continues to grow. Production is expected to start in 2021.  Installed Annual Capacity Current Status Fremont Model S / Model X         90,000 Production Model 3 / Model Y    500,000 Production Shanghai Model 3       250,000 Production Model Y – Construction Berlin Model 3 – In development Model Y – Construction Texas Model Y – Construction Cybertruck – In development United States Tesla Semi – In development Roadster – In development 7 Installed capacity ≠ Current production rate. Production rate depends on pace of factory ramp, supply chain ramp, downtime related to factory upgrades, national holidays and other factors. * Locally-made is defined as (i) cars made in Fremont and delivered in North America and (ii) cars made in China and delivered in China. 1 Premium mid-sized sedan segment in China defined as Audi A4, BMW 3-Series, Mercedes C-Class and Tesla Model 3.

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C O R E   T E C H N O L O G Y Autopilot & Full Self Driving (FSD) Our Autopilot team has been focused on a fundamental architectural rewrite of our neural networks and control algorithms. This rewrite will allow the remaining driving features to be released. In October, we sent the first FSD software update enabled by the rewrite to a limited number of Early Access Program users — City Streets. As we continue to collect data over time, the system will become more robust. Vehicle Software New software functionality was introduced since the start of Q3. In order to make our products safer from unauthorized access, we introduced the ability to enable 2-step verification via a smartphone. Additionally, among many other updates, we improved active suspension comfort, updated Powerwall-to-vehicle charging coordination and added an automated window close function and glovebox PIN access. Our Model Y AWD customers can now purchase a $2,000 software update that improves 0-60 mph time to just 4.3s.     Battery & Powertrain On September 22, we hosted Tesla Battery Day where we described a path to reducing battery pack cost per kWh by 56%, enabling production of a profitable $25,000 vehicle. This, in our view, is a critical component to exceed cost parity with internal combustion engine vehicles. Additionally, due to a simpler cell manufacturing process, we believe capex per GWh of battery capacity should decline by 69% compared to today’s production process.  How our vehicles see an intersection 8 How our Neural Net understands the same intersection (generalized approach for any unmapped intersection)

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O T H E R H I G H L I G H T S Energy Business Our energy storage business reached record deployments of 759 MWh in Q3. Megapack production continued to ramp at Gigafactory Nevada as production volumes more than doubled in Q3. Powerwall demand remains strong and is growing, particularly as our solar business grows as many customers include a Powerwall with their solar installation. Additionally, we are seeing accelerating interest in Powerwall as concerns with grid stability grow, particularly in California. We continue to believe that the energy business will ultimately be as large as our vehicle business. Our recently introduced strategy of low cost solar (at $1.49/watt in the US after tax credit) is starting to have an impact. Total solar deployments more than doubled in Q3 to 57 MW compared to the prior quarter, with Solar Roof deployments almost tripling sequentially. While not yet at scale, we recently demonstrated a ~1.5-day Solar Roof install, as shown below in the photos. For Solar Roof, installation time is a key area of focus to accelerate the growth of this program. We continue to onboard hundreds of electricians and roofers to grow this business. 9 7:30 am Noon 2:00 pm (the next day)

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O U T L O O K Volume Cash Flow Profit Product We have the capacity installed to produce and deliver 500,000 vehicles this year.  While achieving this goal has become more difficult, delivering half a million vehicles in 2020 remains our target. Achieving this target depends primarily on quarter over quarter increases in Model Y and Shanghai production, as well as further improvements in logistics and delivery efficiency at higher volume levels.  We should have sufficient liquidity to fund our product roadmap, long-term capacity expansion plans and other expenses.  For the trailing 12 months, we achieved an operating margin of 6.3%. We expect our operating margin will continue to grow over time, ultimately reaching industry-leading levels with capacity expansion and localization plans underway.  We are currently building Model Y capacity at Gigafactory Shanghai, Gigafactory Berlin and Gigafactory Texas, and remain on track to start deliveries from each location in 2021. Tesla Semi deliveries will also begin in 2021.  We continue to significantly invest in our product roadmap. 10

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B A T T E R Y D A Y H I G H L I G H T S

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Area of improvement Description Range Increase* $/kWh Cost Reduction* $/GWh Capex Reduction* Cell Design After considering every form factor and cell size across quantifiable factors, we deemed 80 mm height by 46 mm diameter cylindrical to be best These dimensions maximize vehicle range (pack level energy density) while minimizing manufacturing and product cost The challenge is that large diameter cylindrical cells easily overheat during supercharging We identified a tab-less design solution to resolve the overheating challenge and simplify manufacturing 16% 14% 7% Cell Factory Electrode Current electrode production process involves mixing liquids with cathode or anode powders and using massive machinery to coat and dry electrode New process allows going directly from cathode or anode powder to an electrode film 0% 18% 34% Winding Larger cells improve winder productivity Incorporates our tab-less design Assembly Large cells moving at high speed with simplification in process steps enables a single production line to have 20 GWh of capacity Formation Leveraging our power electronics to densify and reduce costs of the final charging and testing step of millions of cells Anode Material Silicon is a better anode material than graphite – stores 9x more lithium, but silicon expansion brings challenges Silicon used in anodes today is highly engineered and expensive Raw silicon with our coating design will cost just $1.20/kWh Expansion of silicon is managed by stabilizing surface and by creating an elastic binder network 20% 5% 4% Cathode Material We are taking a diversified cathode approach to maximize available supply options: all usable in our 4680 cells We are planning to manufacture cathode in-house, using far less water and reagents in a simplified production process Focus on local sourcing for each cell factory to avoid unnecessary transportation cost Actively pursuing pathways to vertically integrate lithium production for a portion of supply 4% 12% 16% Cell-Vehicle Integration Current EV design: cells to modules, modules to battery pack, battery pack to vehicle Future EV design: cells directly integrated into vehicle body with giga castings Battery is no longer carried as “luggage”, will provide new utility as a load-bearing frame element This unlocks high-efficiency factories and mechanical structures— best manufacturability, weight, range and cost 14% 7% 8% Projected Total Improvement 54% 56% 69% F I V E A R E A S O F F O C U S 12 * Our current projections.

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P H O T O S & C H A R T S

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G I G A F A C T O R Y   S H A N G H A I   –   M O D E L   Y   F A C T O R Y   ( F O R E G R O U N D ) ;   M O D E L   3   F A C T O R Y   ( B A C K G R O U N D ) 14

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G I G A F A C T O R Y S H A N G H A I – M O D E L Y D I E C A S T 15

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G I G A F A C T O R Y S H A N G H A I – M O D E L Y B O D Y S H O P 16

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G I G A F A C T O R Y S H A N G H A I – M O D E L Y P A I N T S H O P 17

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18 G I G A F A C T O R Y B E R L I N – M O D E L Y F A C T O R Y C O N S T R U C T I O N

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19 G I G A F A C T O R Y T E X A S

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20 M E G A P A C K P R O J E C T AT M O S S L A N D I N G

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Vehicle Deliveries (units) Net Income ($B) K E Y   M E T R I C S   Q U A R T E R L Y  (Unaudited) 21 Operating Cash Flow ($B) Free Cash Flow ($B)

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K E Y   M E T R I C S   T R A I L I N G   1 2   M O N T H S   ( T T M ) (Unaudited) Vehicle Deliveries (units) Operating Cash Flow ($B) Free Cash Flow ($B) Net Income ($B) 22

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F I N A N C I A L S T A T E M E N T S

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In millions of USD or shares as applicable, except per share data Q3-2019 Q4-2019 Q1-2020 Q2-2020 Q3-2020 REVENUES Automotive sales 5,132 6,143 4,893 4,911 7,346 Automotive leasing 221 225 239 268 265 Total automotive revenue 5,353 6,368 5,132 5,179 7,611 Energy generation and storage 402 436 293 370 579 Services and other 548 580 560 487 581 Total revenues 6,303 7,384 5,985 6,036 8,771 COST OF REVENUES           Automotive sales 4,014 4,815 3,699 3,714 5,361 Automotive leasing 117 119 122 148 145 Total automotive cost of revenues 4,131 4,934 3,821 3,862 5,506 Energy generation and storage 314 385 282 349 558 Services and other 667 674 648 558 644 Total cost of revenues 5,112 5,993 4,751 4,769 6,708 Gross profit 1,191 1,391 1,234 1,267 2,063 OPERATING EXPENSES           Research and development 334 345 324 279 366 Selling, general and administrative 596 699 627 661 888 Restructuring and other – (12) – – – Total operating expenses 930 1,032 951 940 1,254 INCOME FROM OPERATIONS 261 359 283 327 809 Interest income 15 10 10 8 6 Interest expense (185) (170) (169) (170) (163) Other income (expense), net 85 (25) (54) (15) (97) INCOME BEFORE INCOME TAXES 176 174 70 150 555 Provision for income taxes 26 42 2 21 186 NET INCOME 150 132 68 129 369 Net income attributable to noncontrolling interests and redeemable noncontrolling interests 7 27 52 25 38 NET INCOME ATTRIBUTABLE TO COMMON STOCKHOLDERS 143 105 16 104 331 Less: Buy-out of noncontrolling interest – – – – 31 NET INCOME USED IN COMPUTING NET INCOME PER SHARE OF COMMON STOCK 143 105 16 104 300 Net income per share of common stock attributable to common stockholders(1)           Basic $ 0.16 $ 0.12 $ 0.02 $ 0.11 $ 0.32 Diluted $ 0.16 $ 0.11 $ 0.02 $ 0.10 $ 0.27 Weighted average shares used in computing net income per share of common stock(1)           Basic 897 902 915 928 937 Diluted 922 935 994 1,036 1,105 S T A T E M E N T O F O P E R A T I O N S (Unaudited) 24 (1) Prior period results have been retroactively adjusted to reflect the five-for-one stock split effected in the form of a stock dividend in August 2020

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B A L A N C E   S H E E T (Unaudited) In millions of USD 30-Sep-19 31-Dec-19 31-Mar-20 30-Jun-20 30-Sep-20 ASSETS Current assets    Cash and cash equivalents 5,338 6,268 8,080 8,615 14,531    Accounts receivable, net 1,128 1,324 1,274 1,485 1,757    Inventory 3,581 3,552 4,494 4,018 4,218    Prepaid expenses and other current assets 893 959 1,045 1,218 1,238       Total current assets 10,940 12,103 14,893 15,336 21,744 Operating lease vehicles, net 2,253 2,447 2,527 2,524 2,742 Solar energy systems, net 6,168 6,138 6,106 6,069 6,025 Property, plant and equipment, net 10,190 10,396 10,638 11,009 11,848 Operating lease right-of-use assets 1,234 1,218 1,197 1,274 1,375 Goodwill and intangible assets, net 537 537 516 508 521 Other non-current assets 1,473 1,470 1,373 1,415 1,436      Total assets 32,795 34,309 37,250 38,135 45,691 LIABILITIES AND EQUITY Current liabilities    Accounts payable       3,468        3,771       3,970        3,638       4,958    Accrued liabilities and other        2,938        3,222        2,825        3,110        3,252    Deferred revenue 1,045 1,163 1,186 1,130 1,258    Customer deposits 665 726 788 713 708    Current portion of debt and finance leases (1) 2,030 1,785 3,217 3,679 3,126      Total current liabilities 10,146 10,667 11,986 12,270 13,302 Debt and finance leases, net of current portion (1) 11,313 11,634 10,666 10,416 10,559 Deferred revenue, net of current portion 1,140 1,207 1,199 1,198 1,233 Other long-term liabilities 2,714 2,691 2,667 2,870 3,049       Total liabilities 25,313 26,199 26,518 26,754 28,143 Redeemable noncontrolling interests in subsidiaries 600 643 632 613 608  Convertible senior notes              —              —  60  44 48 Total stockholders’ equity 6,040 6,618 9,173 9,855 16,031 Noncontrolling interests in subsidiaries 842 849 867 869 861       Total liabilities and equity 32,795 34,309 37,250 38,135 45,691 (1) Breakdown of our debt is as follows:    Vehicle and energy product financing (non-recourse) 3,702 4,183 4,022 4,043 4,141    Other non-recourse debt 155 355 708 1,415 605    Recourse debt 7,882 7,263 7,600 7,106 7,448       Total debt excluding vehicle and energy product financing 8,037 7,618 8,308 8,521 8,053 25

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In millions of USD Q3-2019 Q4-2019 Q1-2020 Q2-2020 Q3-2020 CASH FLOWS FROM OPERATING ACTIVITIES Net income 150  132  68  129  369  Adjustments to reconcile net income to net cash provided by (used in) operating activities: Depreciation, amortization and impairment 530  577  553  567  584  Stock-based compensation 199  281  211  347  543  Other 69  204  175  167  269  Changes in operating assets and liabilities, net of effect of business combinations (192) 231  (1,447) (246) 635  Net cash provided by (used in) operating activities 756  1,425  (440) 964  2,400  CASH FLOWS FROM INVESTING ACTIVITIES Capital expenditures (385) (412) (455) (546) (1,005) Purchases of solar energy systems, net of sales (25) (37) (26) (20) (16) Purchase of intangible assets               —                —                —                —  (5) Receipt of government grants               —  46  1  —  —  Business combinations, net of cash acquired (76)               —                —                —  (13) Net cash used in investing activities (486) (403) (480) (566) (1,039) CASH FLOWS FROM FINANCING ACTIVITIES Net cash flows from debt activities (55) (591) 544  164  (630) Collateralized lease repayments (83) (87) (97) (71) (56) Net borrowings (repayments) under vehicle and solar financing 183  478  (160) 18  99  Net cash flows from noncontrolling interests – Auto 30  19  (8) (3) (31) Net cash flows from noncontrolling interests – Solar (28) 6  (40) (42) (49) Proceeds from issuances of common stock in public offerings, net of issuance costs               —                —  2,309                —  4,973  Other 71  96  160  57  144  Net cash provided by (used in) financing activities 118  (79) 2,708  123  4,450  Effect of exchange rate changes on cash and cash equivalents and restricted cash (11) 14  (24) 38  86  Net increase in cash and cash equivalents and restricted cash 377  957  1,764  559  5,897  Cash and cash equivalents and restricted cash at beginning of period 5,449  5,826  6,783  8,547  9,106  Cash and cash equivalents and restricted cash at end of period 5,826  6,783  8,547  9,106  15,003  S T A T E M E N T   O F   C A S H   F L O W S  (Unaudited) 26

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In millions of USD or shares as applicable, except per share data Q3-2019 Q4-2019 Q1-2020 Q2-2020 Q3-2020           Net income attributable to common stockholders (GAAP) 143 105 16 104 331 Stock-based compensation expense 199 281 211 347 543 Net income attributable to common stockholders (non-GAAP) 342 386 227 451 874 Less: Buy-out of noncontrolling interest – – – – 31 Net income used in computing EPS attributable to common stockholders (non-GAAP) 342 386 227 451 843         EPS attributable to common stockholders, diluted (GAAP)(1) 0.16 0.11 0.02 0.10 0.27 Stock-based compensation expense per share(1) 0.21 0.30 0.21 0.34 0.49 EPS attributable to common stockholders, diluted (non-GAAP)(1) 0.37 0.41 0.23 0.44 0.76 Shares used in EPS calculation, diluted (GAAP and non-GAAP)(1) 922 935 994 1,036 1,105 Net income attributable to common stockholders (GAAP) 143 105 16 104 331 Interest expense 185 170 169 170 163 Provision for income taxes 26 42 2 21 186 Depreciation, amortization and impairment 530 577 553 567 584 Stock-based compensation expense 199 281 211 347 543 Adjusted EBITDA (non-GAAP) 1,083 1,175 951 1,209 1,807 Total revenues 6,303 7,384 5,985 6,036 8,771 Adjusted EBITDA margin (non-GAAP)(2) 17.2% 15.9% 15.9% 20.0% 20.6%         Automotive gross margin (GAAP) 22.8% 22.5% 25.5% 25.4% 27.7% Less: Total regulatory credit revenue recognized 2.0% 1.6% 5.5% 6.7% 4.0% Automotive gross margin excluding regulatory credits (non-GAAP) 20.8% 20.9% 20.0% 18.7% 23.7% R e c o n c I l I a t I o n   o f   G A A P   t o   N o n – G A A P   F I n a n c I a l   I n f o r m a t I o n (Unaudited) 27 In millions of USD 4Q-2017 1Q-2018 2Q-2018 3Q-2018 4Q-2018 1Q-2019 2Q-2019 3Q-2019 4Q-2019 1Q-2020 2Q-2020 3Q-2020 Net cash provided by (used in) operating activities (GAAP) 510 (398) (130) 1,391 1,235 (640) 864 756 1,425 (440) 964 2,400 Capital expenditures (787) (656) (610) (510) (325) (280) (250) (385) (412) (455) (546) (1,005) Free cash flow (non-GAAP) (277) (1,054) (740) 881 910 (920) 614 371 1,013 (895) 418 1,395                           In millions of USD 4Q-2017 1Q-2018 2Q-2018 3Q-2018 4Q-2018 1Q-2019 2Q-2019 3Q-2019 4Q-2019 1Q-2020 2Q-2020 3Q-2020 Net cash (used in) provided by operating activities – TTM (GAAP) (61) (389) (319) 1,373 2,098 1,856 2,850 2,215 2,405 2,605 2,705 4,349 Capital expenditures – TTM (3,415) (3,518) (3,169) (2,563) (2,101) (1,725) (1,365) (1,240) (1,327) (1,502) (1,798) (2,418) Free cash flow – TTM (non-GAAP) (3,476) (3,907) (3,488) (1,190) (3) 131 1,485 975 1,078 1,103 907 1,931 (1) Prior period results have been retroactively adjusted to reflect the five-for-one stock split effected in the form of a stock dividend in August 2020 (2) Adjusted EBITDA margin is Adjusted EBITDA as a percentage of total revenues

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A D D I T I O N A L   I N F O R M A T I O N WEBCAST INFORMATION Tesla will provide a live webcast of its third quarter 2020 financial results conference call beginning at 2:30 p.m. PT on October 21, 2020 at ir.tesla.com. This webcast will also be available for replay for approximately one year thereafter.   CERTAIN TERMS When used in this update, certain terms have the following meanings. Our vehicle deliveries include only vehicles that have been transferred to end customers with all paperwork correctly completed. Our energy product deployment volume includes both customer units installed and equipment sales; we report installations at time of commissioning for storage projects or inspection for solar projects, and equipment sales at time of delivery. “Adjusted EBITDA” is equal to (i) net income (loss) attributable to common stockholders before (ii)(a) interest expense, (b) provision for income taxes, (c) depreciation, amortization and impairment and (d) stock-based compensation expense, which is the same measurement for this term pursuant to the performance-based stock option award granted to our CEO in 2018. “Free cash flow” is operating cash flow less capital expenditures. NON-GAAP FINANCIAL INFORMATION Consolidated financial information has been presented in accordance with GAAP as well as on a non-GAAP basis to supplement our consolidated financial results. Our non-GAAP financial measures include non-GAAP automotive gross margin, non-GAAP net income (loss) attributable to common stockholders, non-GAAP net income (loss) attributable to common stockholders on a diluted per share basis (calculated using weighted average shares for GAAP diluted net income (loss) attributable to common stockholders), Adjusted EBITDA, Adjusted EBITDA margin, and free cash flow. These non-GAAP financial measures also facilitate management’s internal comparisons to Tesla’s historical performance as well as comparisons to the operating results of other companies. Management believes that it is useful to supplement its GAAP financial statements with this non-GAAP information because management uses such information internally for its operating, budgeting and financial planning purposes. Management also believes that presentation of the non-GAAP financial measures provides useful information to our investors regarding our financial condition and results of operations so that investors can see through the eyes of Tesla management regarding important financial metrics that Tesla uses to run the business, and allowing investors to better understand Tesla’s performance. Non-GAAP information is not prepared under a comprehensive set of accounting rules and therefore, should only be read in conjunction with financial information reported under U.S. GAAP when understanding Tesla’s operating performance. A reconciliation between GAAP and non-GAAP financial information is provided above.   FORWARD-LOOKING STATEMENTS Certain statements in this update, including statements in the “Outlook” section; statements relating to the future development, production capacity and output rates, demand and market growth, deliveries, deployment, safety, range and other features and improvements, and timing of existing and future Tesla products and technologies such as Model 3, Model Y, Cybertruck, Tesla Semi, Roadster, Autopilot and Full Self Driving, our energy products and services such as Megapack, Solar Roof and Powerwall, and the battery cells we are developing and related technologies; statements regarding operating margin, spending and liquidity targets; statements regarding manufacturing and procurement improvements, cost reductions and efficiencies; statements regarding construction, expansion, improvements and/or ramp at the Tesla Factory, Gigafactory Shanghai, Gigafactory Berlin and Gigafactory Texas; and statements regarding our hiring targets are “forward-looking statements” that are subject to risks and uncertainties. These forward-looking statements are based on management’s current expectations, and as a result of certain risks and uncertainties, actual results may differ materially from those projected. The following important factors, without limitation, could cause actual results to differ materially from those in the forward-looking statements: uncertainties in future macroeconomic and regulatory conditions arising from the current global pandemic; the risk of delays in launching and manufacturing our products and features cost-effectively; our ability to grow our sales, delivery, installation, servicing and charging capabilities and effectively manage this growth; consumers’ willingness to adopt electric vehicles generally and our vehicles specifically; the ability of suppliers to deliver components according to schedules, prices, quality and volumes acceptable to us, and our ability to manage such components effectively; any issues with lithium-ion cells or other components manufactured at Gigafactory Nevada; our ability to build and ramp Gigafactory Shanghai, Gigafactory Berlin and Gigafactory Texas in accordance with our plans; our ability to procure supply of battery cells, including through our own manufacturing; risks relating to international expansion; any failures by Tesla products to perform as expected or if product recalls occur; the risk of product liability claims; competition in the automotive and energy product markets; our ability to maintain public credibility and confidence in our long-term business prospects; our ability to manage risks relating to our various product financing programs; the unavailability, reduction or elimination of government and economic incentives for electric vehicles and energy products; our ability to attract and retain key employees and qualified personnel and ramp our installation teams; our ability to maintain the security of our information and production and product systems; our compliance with various regulations and laws applicable to our operations and products, which may evolve from time to time; risks relating to our indebtedness and financing strategies; and adverse foreign exchange movements. More information on potential factors that could affect our financial results is included from time to time in our Securities and Exchange Commission filings and reports, including the risks identified under the section captioned “Risk Factors” in our quarterly report on Form 10-Q filed with the SEC on July 28, 2020. Tesla disclaims any obligation to update information contained in these forward-looking statements whether as a result of new information, future events, or otherwise. 28

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