Cytodyn Inc (CYDY)

[finesand]

Comparison HIV-1 Anti-infective antibodies (update)

See also earlier 2018-04-23 HIV-1 Anti-infective antibodies review part-1.

Also see a little elaboration on HIV-1 Tropism 2018-05-10 - R5- and X4-Tropism, Safety Profiles

See also comparison of Cytodyn with TaiMed/THERF, as well as with cheap Pharmasset buyout
- TaiMed/Theratechnologies Original Comparison by z_smith, part-1, part-2
- Theratechnologies (THERF) Details
- Historical Pharmasset Cheap Buyout in Early Stage

Competitors
- Maraviroc targeting host CCR5 receptor, MDR 3; ViiV Healthcare + GSK, approved in 2007 and 2016 for adolescents
- Pro 140 targeting host CCR5 receptor, MDR 2; Cytodyn, Combo Phase 3 until September 2018: R > 0.5log10 up to 1.8log10
- Ibalizumab (IZ) targeting host CD4 receptor, MDR 3; TaiMed+THERF approved 2016-2018, 46% VL reduction, AEs + SAEs
- Fostemsavir targeting HIV-1 gp120 protein , MDR 3; ViiV Healthcare + GSK, phase 3 until 2020: 18% AEs + SAEs, R 0.62 log10 c/mL

MDR = multi-drug resistant, lower is better due to earlier treatment and more patients

Maraviroc
- Targeting host CCR5 Coreceptor, blocking CCR5-tropic HIV-1 from entering
- MDR 3
- Aproved for adults in 2007 and for children over 2 years old adolescents in 2016.
- Many very serious side effects.
- Use for HIV only together with other HAART medicine.
- See https://www.viivhealthcare.com/media/press-releases/2016/october/viiv-healthcare-announces-fda-approval-of-selzentry-maraviroc-for-use-in-children-and-adolescents-living-with-hiv.aspx
- See https://www.nejm.org/doi/full/10.1056/NEJMoa0803152

Pro 140, owner Cytodyn
- Targeting host CCR5 Coreceptor, blocking CCR5-tropic HIV-1 from entering
- MDR 2. Spec: May apply for MDR 0 post mono trial
- Weekly or biweekly subcutaneous self-administered PRO 140 injection
- Viral Supression in short range study of 0.5log10 up to 1.8log10, undetectable long term
- Undisputed in scientific community at least since 2000, covered by peer reviewed papers and cited in reviews
- Safety profile is extraordinary, especially since Pro 140 does not impact CCR5 host receptor normal operations
- No detected Pro 140 antibodies in any patient.

- Safety Profile re 2017-02 Combo n=16
-- No drug related SAEs
-- No discontinuation due to AEs, 25-50% drug related if at all
-- No pattern of toxicity
-- No dose-limiting toxicity in studies
-- Mono trial will clarify safety profile in more details

- Efficacy re 2017-02 Combo n=16
-- R 0.9log10 @ 162mg weekly
-- R 1.2log10 @ 324mg biweekly
-- R 1.5log10 @ 324mg weekly
-- Max impact after one week post injection
-- No PRO 140 antibodies detected in any subject!
-- No change in co-receptor tropism at virologic rebound (5/16)

- Efficacy re 2018-02 CD02 Pivotal Combo n=52
-- PE CD02 Combo: R > 0.5log10 @ 350mg, 1 week after 1 subcutaneous injection of PRO 140
-- PE reached in CD02 Combo Part-1
-- Details via poster on 6/9 @ ASM Microbe 2018

- CD02 Pivotal Combo Phase 3, 52 patients for 25 weeks, up until September 2018
-- Part-1 Efficacy R > 0.5log10 1 week after 1 350mg injection, reached
-- Part-2 OBT phase fro 24 weeks
-- Weekly 350mg subcutaneous injection of PRO 140
-- Safety data of CD03 Mono to support rolling BLA submission, orig from 100pt.
-- 6/9/18 CD02 Pivotal Phase 3 Endpoint Achieved (ASM Microbe late breaker)
-- 3Q18: BLA Submission for CD02 Combo (rolling BLA)
-- 2019: CD02 HIV Combination Therapy Approval w/ BTD
-- ClinicalTrials.gov Identifier: NCT02483078

- CD03 Mono Phase 3, 300 patients for 48 weeks
-- Enrollment started in December 2016 to complete 4Q18.
-- Completion date around 2Q19 - 3Q19, depending on enrollment.
-- Provides safety data for CD02 Combo BLA submission, orig from 100 patients
-- Primary Endpoint: Responder rate above 70%
-- Secondary Endpoint: Non-responders can resume orig HAART therapy w/o resistance
-- Currently exploring a high-dose arm, with a 50% increase is dosage to evaluate
.. an increased response rate among certain patients
-- Expects to increase the number of sites in order to accelerate enrollment following
the completion of enrollment of the pivotal combination therapy trial & availability of additional capital.
-- 4Q18: CD03 Phase 2b/3 Mono Investigative Trial Readout (probably later, CD03 completion around 2Q19)
-- ClinicalTrials.gov Identifier: NCT02859961

- CD01 Extension Study
-- 6/9 patients completed over 2.5 years on PRO 140 monotherapy, since around 2015.01

- Mono Phase 2 Study, 44 patients for ~5 weeks, successfully completed
- Paper https://www.ncbi.nlm.nih.gov/pubmed/20377413?dopt=Abstract
-- https://www.tandfonline.com/doi/abs/10.1080/15284336.2018.1452842?journalCode=yhct20
-- ClinicalTrials.gov Identifier: NCT00642707

Ibalizumab (IZ) Comparison Details, owner TaiMed
- Targeting host CD4 receptor, blocking HIV-1 from entering
- MDR 3
- TaiMed MCAP $2.2B
- US + Canada retail sales partner Theratechnologies MCAP $697.29M
-- THERF got a 5-10% royalty deal w/ TaiMed, but license 'only' for US and Canada
-- THERF to pay $10 million once annual sales of $200 million are reached in the US.
-- That goes up to a $100 million if they can break the $1 billion mark.
- Total $2.9B MCAP
- TaiMed MCAP rose to ~$1.6B shortly after filing of their BLA
- TaiMed was approved by the FDA in March, 2018, their market cap is USD$2.2B now.
- IZ trial had only 40 patients in their ph3 and no MONO objective, only COMBO
- IZ 43% achieved HIV RNA suppression after 24 weeks of Trogarzo.
- IZ common adverse events: diarrhea, dizziness, nausea and rash.
- IZ severe adverse events: rash and Immune Reconstitution Inflammatory Syndrome (IRIS),
..a condition in some HIV patients where the immune system recovers but then responds
..to a previously acquired opportunistic infection with an overwhelming immune (inflammatory) response.
- IZ is currently approved and roughly equivalent in terms of market size as PRO-140,
but actually should have smaller market size see below

IZ overall market size is smaller to Pro 140 due to
- COMBO only, Pro-140 applies for Mono as well and GvHD
- 3 Drug MDR, instead of 2 Drug MDR for Pro-140. Earlier treatment & more patients for Pro 140.
- IM IV not approved yet, also not “self-administration” route like SC injection of Pro-140,
which is a significant financial savings and care-plan/logistical advantage
- 43% Viral Suppression instead of nearly 99% w/ Pro-140
- Having AEs and even SAEs, Pro-140 has only little AEs if drug related at all

Fostemsavir Comparison, owner ViiV/GSK
- Targeting HIV-1 gp120 protein, blocking HIV-1 from entering
- Fostemsavir look very interesting , but phase 3 for mostly very sick MDR 3 patients only.
- After 24 weeks 54% of patients with viral load below 40copies/mill
- Information about side effect is still not complete.

371 total patients during study with Fostemsavir.
- 17 deaths during study ( 5% ) - due to progression of HIV.
- 91% of patients developed at least one side effect.
- 18% of patients developed mild , moderate-severe side effects.
- 9 patients ( about 2.5% ) developed severe side effects.
- 21 patients ( about 6% ) had side effects that caused them to leave the study.
- Phase 3 to be completed in 2020, as noted in excerpt, see https://www.viivhealthcare.com/media/press-releases/2017/october/viiv-healthcare-announces-positive-phase-3-results-from-the-brighte-study-of-fostemsavir-in-heavily-treatment-experienced-patients-with-hiv.aspx

Fostemsavir might be more a competition to Ibalizumab for now, but not really to Pro 140
When using Pro 140 most of CCR5 patients will not regress to MDR 3 most likely.
Most likely: Fostemsavir could be used for very sick MDR 3 patience for non-CCR5 HIV-1