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Case Study
fenebrutinib
[Link]
fenebrutinib
oral BTK inhibitor
Ph. III for multiple sclerosis
from ATP site-directed compound libraries + optimization
Clinical data release, May 16, 2023
GENENTECH, SOUTH SAN FRANCISCO, CA

VIEW ONLINE

A Reversible, Brain-Penetrant BTK Inhibitor Reduces

Brain Lesions In Multiple Sclerosis (MS)
Genentech recently announced that fenebrutinib (GDC-0853), a noncovalent Bruton’s
tyrosine kinase (BTK) inhibitor, rapidly reduced new brain lesions in Ph. II clinical
trials for relapsing multiple sclerosis (RMS) and would be entering Ph. III. Following
the success of BTK inhibitors in oncology, BTK has been a hotly pursued target to treat
chronic autoimmune diseases, with multiple companies evaluating BTK inhibitors in
a range of clinically and commercially important indications. Other candidates for
MS, evobrutinib, tolebrutinib, remibrutinib, and orelabrutinib, are all covalent BTK
inhibitors, leaving fenebrutinib as the only noncovalent inhibitor in late clinical evaluation
for MS. While evobrutinib, tolebrutinib, orelabrutinib, have all been placed on clinical hold
in Ph. II or III for MS due to drug-induced liver injury cases, fenebrutinib’s apparently
superior selectivity and safety profile, combined with it having the highest potency of all
BTK inhibitors under evaluation in Ph. III clinical trials for MS, have moved it ahead of
covalent competitors as a potential treatment for rheumatoid arthritis, systemic lupus
erythematosus, and now MS. This article reviews the unique properties of fenebrutinib
including its long residence time, brain penetration in humans, and highlights from its
discovery and development now spanning over a decade.

A list of BTK inhibitors currently under evaluation as MS therapeutics in clinical trials.

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 Reviewer Comments
Reviewer Charles Cole notes, “BTK is a well-known target in medicinal chemistry - in fact,
a recent book by Nathaniel Vardi, ‘For Blood and Money,’ grippingly details the discovery
and development of the first-to-market BTK inhibitors, ibrutinib and acalabrutinib. The
most notable feature of fenebrutinib is the selected indications in clinical trials. Most
BTKi’s focus primarily on the treatment of mantle cell lymphoma and similar oncology
indications. Fenebrutinib, rather, is currently under investigation in multiple traditional
autoimmune disease indications, including multiple sclerosis, rheumatoid arthritis, systemic
lupus erythematosus and chronic spontaneous urticaria. While these indications are tough,
requiring strict safety profiles due to long-term treatment, fenebrutinib has the chance to
become the first approved BTKi for an autoimmune disorder.”

Reversible BTK Inhibition Enhances Efficacy In Oncology And

Safety Across Indications
While we have recently covered the importance of the reversible mode of action for
pirtobrutinib’s efficacy in oncology, it also contributes to pirtobrutinib’s safety profile.
Irreversible BTK inhibitors like ibrutinib (Imbruvica®) form covalent bonds with the
Cys481 residue in the binding site of BTK, which is present in several other kinases.
Although targeted covalent inhibitors can be highly potent and have extended durations of
action, off‑target toxicities with covalent BTK inhibitors have been associated with high
discontinuation rates and the potential immunogenicity of covalently bound drug-receptor
complexes likely contribute to the drug-induced liver injury observed with many covalent
BTK inhibitors in MS so far. Ibrutinib, for example, has off-target interactions with at least
seven other kinases, including BLK, BMX, ITK, TEC, EGFR, ERBB2, and JAK3, and off‑target
engagement of ibrutinib with ERBB2/HER2 and ERBB4/HER4 has been implicated in atrial
fibrillation and atrial flutter (4% grade ≥3). While more selective second-generation covalent
BTK inhibitors like zanubrutinib (Brukinsa®) and acalabrutinib (Calquence®) appear to be
tolerated better than ibrutinib, their use has been discontinued in clinical trials at similar
rates due to adverse events. “Fenebrutinib may afford a better toxicity profile by removing
dependence on C481, a common residue in other tyrosine kinases, and offer broader
kinome selectivity overall,” says Charles Cole. The noncovalent nature of the molecule and
further kinase selectivity attributed to its induced fit binding mode combine to result in
fenebrutinib’s greater selectivity for BTK in vitro against covalent inhibitors including
ibrutinib, acalabrutinib, tirabrutinib, BMS-986142, and evobrutinib. These theoretical safety
advantages so far appear to translate to a favorable human safety profile for fenebrutinib,
as Genentech states that fenebrutinib has a larger clinical safety database than any other
BTK inhibitor under evaluation in MS, with the only known risk causally associated with it
being asymptomatic, reversible elevation of two liver aminotransferases, ALT and AST, with
no Hy’s law cases. While reversible liver enzyme elevations have been suggested to be a class
effect, the rates of liver injury are not consistent across BTK inhibitors, and may also be
related to reactivation of latent hepatitis B infection.

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 Mechanism Of Action In Multiple Sclerosis
In brain autospies from MS patients, BTK+ cells have been found to be increased
around brain lesions, attributable to BTK protein in microglia. Microglia recruit
and maintain adaptive immune cells into the CNS, including brain-homing B
cells, which drive CNS damage in MS. While B cell-depleting anti-CD20 antibodies
like ocrelizumab and rituximab have long been effective in MS, they are not brain penetrant
and likely cannot target CNS-resident B cells. Since small molecules are more likely to be
CNS-penetrant than antibodies, small molecule inhibition of intracellular BTK offers the
potential to target CNS-resident B cells, since BTK inhibition blocks B cell receptor (BCR)
signalling. Additionally, BTK inhibition reduces Fcγ receptor (FcγR) signaling in macrophages
and microglia, potentially addressing several mechanisms that drive immunopathology in
the CNS. BTK inhibition can suppress key processes in relapsing and progressive forms of
MS, including pathological activation of B cells, infiltration of the CNS by lymphocytes,
leptomeningeal inflammation, pro-inflammatory microglial activation, and demyelination.

A Highly Selective Starting Point From ATP Site-Directed

Compound Libraries
In the early 2000’s, a team at kinase-focused Yale spinout CGI Pharmaceuticals (acquired
by Gilead in 2010) led by Kevin Currie screened ATP site-directed compound
libraries against a panel of 16 kinases to identify a selective imidazo[1,2-a]pyrazine
scaffold (CGI560, US7393848B2). While CGI560 had a modest IC50 of 400 nM against BTK,
it possessed >10-fold selectivity over the other 15 kinases in the panel. Replacing the
imidazopyrazine hinge binder with bioisosteric hinge binding units and optimization led
to CGI1746 (WO2006099075) which possessed a potent BTK IC50 of 1.9 nM and excellent BTK
selectivity showing no significant activity against the 468 discrete targets it was tested

O N
O N H
H N S
N N N HN N
H HN N
O
N O
HN N
O
H
O
N
N O
N
O

CGI560 CGI1746 GDC-0834

BTK IC50 = 400 nM BTK IC50 = 1.9 nM improved preclinical PK
>10x selective over 15 kinases poor DMPK/ADME rapid amide hydrolysis in clinic

O N HO
O N HO O N HO N
N N
N
N N HN
HN HN
O
N O N O N
N N
F

N
N N

N
N N

O
O O

fenebrutinib (GDC-0853) compound 12 G-278

long drug-target residence time in vitro hepatotoxicity mitigated improved metabolic profile
well-tolerated & efficacious in Ph. I/II high rat clearance dog hepatotoxicity

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 against, with >980x-selectivity over the next most sensitive kinase, BMX. The 1.8 Å crystal
structure of the molecule bound to the human BTK kinase domain (PDB: 3OCS) revealed that
CGI1746 bound to the enzyme in an inactive conformation in which the activating tyrosine
residue (Tyr551) was unphosphorylated and sequestered from solvent. Binding of CGI1746
induced the formation of a large pocket in the SH3 domain, dubbed the H3 pocket, which
was occupied by the critical t-butylphenyl moiety of CGI1746.

A Genentech Partnership And ADME Optimization To GDC-0834

In 2006, after the CGI1746 patent filing (WO2006099075), Genentech signed a $25M upfront,
$500M partnership agreement with CGI to collaborate on an “unidentified target” (now
known to be BTK). While CGI1746 was highly potent and selective, it displayed unfavorable
ADME properties in rats (rat CL = 87 mL/min/kg, F = 5%). The Genentech & CGI teams, led
by Wendy Young, sought molecules with PK suitable for human dosing. Substitution of the
H3-pocket’s t-butylphenyl group with a tetrahydrobenzothiophene moiety and increasing
the polarity of the solvent-exposed region with a dimethyl-piperazin-3-one-2-yl group
produced GDC-0834, which had a good balance of biochemical and cellular potency with
acceptable PK properties (BTK Ki = 6 nM, CD86 cell-based IC50 = 60 nM, rat CL = 4.4 mL/
min/kg, F = 35%). GDC-0834 maintained the favorable selectivity profile as CG11746 with
minimal to no off-target receptor activity when screened against a panel of 30 targets.

Surprising Aldehyde Oxidase-Mediated Amide Hydrolysis

Of GDC-0834 In Healthy Volunteers
While GDC-0834 had good rodent PK, the in vitro to in vivo correlation varied depending
on the preclinical species, making human PK prediction challenging. Additionally, the use
of multiple in vitro clearance assays revealed significant non-CYP–mediated metabolism of
GDC-0834, and the predicted range of human clearance was wide. A single dose IND was
therefore filed with GDC-0834 to evaluate PK in healthy volunteers. In the human study,
rapid enzymatic cleavage of the amide bond linking the tetrahydrobenzothiophene moiety
to the rest of the molecule resulted in insufficient exposure to the parent drug as well as
release of an aniline as the major metabolite, leading to discontinuation of the molecule.
Surprisingly, the amide hydrolysis was found to be due to both aldehyde oxidase (AO) and
carboxyesterase (CES), with the aldehyde oxidase amide bond cleavage proposed to occur
through a non-oxidative mechanism involving the molybdenum cofactor (human AO
PDB: 4UHW).
R
NH
S
O
Hydrolysis is proposed to
S O
occur via the molybdenum
O S Mo O
H H cofactor (MoCo) of
N S H aldehyde oxidase (AO).
HN
O
O
H 2N N N O P
H H HO
OH

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 Mitigating Amide Hydrolysis Through Cyclization
The Genentech/CGI team was able to identify more metabolically stable compounds
by cyclizing the amide onto the thiophene or related heterocycles, forming 6-5-5 tricycles.
Removing the exposed N-H hydrogen bond donor and increasing the molecules’ rigidity
increased potency and permeability.

H-bonding
(potency) reduce amide hydrolysis

O N HO
N
O N N
H HN
N S O
HN N N
O
F

N dipole interaction w/ C=O

H (potency)
O
N N
N weakly basic
solvent-exposed group
O

GDC-0834 G-278
improved preclinical PK improved metabolic profile
rapid amide hydrolysis in clinic dog hepatotoxicity

Picomolar Compound G-278 Identified, But With Dose-Limiting

Toxicities In Vivo
Introduction of a hydroxyl group to the central toluene group greatly increased lipophilic
efficiency, reducing lipophilicity while increasing potency through new water-mediated
hydrogen bonds with D539 and K430. A substituted pyridinopiperazine group was found to
offer significant kinetic solubility, and an oxetanyl group off of the piperazine was found to
increase permeability among the amines likely thanks to the reduced basicity of the resulting
piperazines (pKa of 6.3 for oxetane-substituted amine vs. 7.8 for methylpiperazine analogs),
but reduced solubility. A potency breakthrough came from fluorination of the linker benzene,
which engages a backbone carbonyl of G409 with a dipole-dipole interaction, increasing
cellular potency by 5-13-fold. While the resulting compound G-278 (AMCL 2017 compound
20, JMC 2018 compound 6) displayed excellent affinity and biochemical potency (BTK Ki
= 0.69 nM, IC50 = 4 nM), whole blood potency (35 nM), metabolic stability (HHep <6 mL/
min/kg), high permeability, excellent kinase selectivity, and an acceptable preclinical PK
profile including oral bioavailability (F% = 27 in rat), dose-limiting toxicities were observed
in rat and dog tolerability studies with low safety margins. In rats, unusual pancreatic
toxicities were observed, while in dogs, hepatotoxicity was observed, characterized by ALT
and AST liver enzyme elevations, cell infiltrates in the liver, Kupffer cell hypertrophy, and
hepatocellular degeneration.

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 Lowering LogD And Avoiding Strongly Basic Groups To
Address Hepatotoxicity
A hepatocyte cytotoxicity assay with cryopreserved human hepatocytes to was used to
identify high-risk compounds, and an in silico model was generated based on 70 molecules
to help predict hepatocyte cytotoxicity. The model suggested that the pKa of most basic
nitrogen, the logP, and plasma protein binding (PPB) were cytotoxic risk factors with
a strongly basic nitrogen being the most significant risk factor. Optimization therefore
focused on lowering logD while avoiding strongly basic groups. Replacing the central aryl
ring with a pyridine heterocycle lowered the logD (pH 7.4) from 3.1 to 2.0 and an increased
predicted stability in human liver microsomes from 12.3 to 8.1 mL/min/kg. Incorporating the
dimethyl-substituted cyclopentyl group improved whole blood (WB) potency, lowering the
WB CD69 IC50 from 55 to 15 nM while maintaining metabolic stability and physicochemical
properties. These modifications resulted in compound 12, which successfully avoided toxicity
in primary human hepatocytes but unfortunately exhibited high plasma clearance with a Clp
of 165 mL/min/kg and a short half-life of 0.4h in cassette rat PK study, so SAR evaluation
continued to improve in vivo stability.

O N HO
O N HO O N HO N
N N N
N N HN
HN HN WB N O
O N O potency N
N N
F
lower
N
N N logD

N conformational restriction &

N N residence time

O
O O

G-278 compound 12 fenebrutinib (GDC-0853)

logD (pH 7.4) = 3.1 logD (pH 7.4) = 1.9 logD (pH 7.4) = 1.6
WB CD69 IC50 = 36.5 nM WB CD69 IC50 = 15.4 nM WB CD69 IC50 = 8.4 nM
dog hepatotoxicity 4.4 h residence time 16.1 h residence time
rat Clp = 165 mL/min/kg rat Clp = 27.4 mL/min/kg
in vitro hepatotoxicity mitigated well-tolerated & efficacious in Ph. I/II

A “Magic” Methyl Group Creates A “Covalent-Like” Long

Residence Time Molecule With Improved PK
Modeling revealed room for the addition of a 2-methyl group to the piperazine ring
to enhance van der Waals contacts with Btk and impart conformational restriction of
the motif. Remarkably, 2-methyl incorporation resulting in GDC-0853 (fenebrutinib)
significantly increased drug-target residence time (from 4.4 h to 16.1 h) in a jump dilution
experiment, significantly reduced plasma clearance (e.g. 27.4 mL/min/kg in rat), and
increasing in the rodent half-life from 0.4 h to 2.2 h (rat PK estimate), while the drug
bioavailability and volume distribution were not significantly changed. Given the slow
resynthesis rate of BTK protein (BTK half-life = 12 h), the 16 h residence time suggests
that the noncovalent fenebrutinib could have a functional duration of action comparable to
covalent molecules, without the haptenization risk of covalents.

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 Binding Mode
PDB: 5VFI - A 1.59-Å resolution X-ray cocrystal structure of fenebrutinib bound to BTK was
solved. The central pyridone is the hinge binder, and the hydrophobic tricyclic ring system
of the drug displaces Tyr551 of the activation loop 18 Å from its position in apo-Btk which
contributes substantially to its potency and kinase selectivity.

Preclinical Properties Supporting Candidate Nomination

With its strong whole blood B cell CD60 potency (IC50 = 8.4 nM), clean cytotoxicity profile in
primary human hepatocytes (IC50 > 300 uM), and the most BTK-selective profile for a BTK
kinase inhibitor reported to date, fenebrutinib (compound 29) was a strong contender for
nomination as a clinical candidate. Key preclinical properties included:

• Primary cell activity: The drug inhibited anti-IgM induced BTK phosphorylation (IC50 =
3.1 nM) and FcγRIII-triggered TNFα production in monocytes (IC50 = 1.3 nM).
• In vivo efficacy in rat B and myeloid cell-dependent inflammatory arthritis model (2
mpk PO BID)
• Favorable PK: 85% bioavailability in dogs, 3.8 h half-life (Clp = 10.9 mL/min/kg, Vd =
2.96 L/kg), 65% F in rats, 2.2 h half-life (Clp = 27.4 mL/min/kg, Vd = 5.42 L/kg)
• In vivo safety: a high no observed adverse effect level (NOAEL) in dogs (most sensitive
species), >80-fold higher than targeted efficacious exposure (human WB CD69 IC70
coverage for >12 h)
• Clean in vitro safety profile: no binding >50% in 41 receptor panel at 10 µM, hERG
channel inhibition (functional) IC50 > 30 µM, hNav1.5 channel inhibition = 0.6% at 1
µM and 1.9% at 10 µM, hCav1.2 channel inhibition (functional) = 1.5% at 1 µM
and 3.8% at 10 µM, Ames negative, MNT (HPBLs) negative, cytotoxicity in human
hepatocytes IC50 > 300 µM, CYP 3A4, 1A2, 2C19, 2D6, 2D9 inhibition IC50s > 5 µM
• Physicochemical properties: MW = 664.8, pKa (25 ˚C) = 5.03, 3.69, 1.05; logP (neutral) =
3.3, logP (cationic) = 1.34, solubility (0.1 N HCl, 37 ˚C) = 35.9 mg/mL, (water, 37 ˚C) =
0.003 mg/mL

On-Target Pancreatic Toxicity Found To Be Rat-Specific

A significant preclinical concern was the observation of pancreatic lesions in islets
at clinically relevant doses in Sprague-Dawley rats across structurally distinct BTK
inhibitors including ibrutinib and spebrutinib. Given the differences in sensitivity across
species and rat strains, and evidence in humans with X-linked agammaglobulinemia (XLA),
a genetic disease linked to BTK mutations, it was concluded that the toxicity, while likely
a class effect, was not relevant to humans. This was likely a relief given the likely non-
monitorable nature of such a toxicity if it were to manifest in humans.

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 Safety And Efficacy Demonstrated In Ph. I And Ph. II Clinical Trials
Fenebrutinib was well-tolerated with no serious or dose-limiting effects in a placebo-
controlled Ph. I study with healthy volunteers, which indicated suitability for its
development as a treatment for autoimmune diseases, with PK/PD data supporting oral
activity of fenebrutinib at 100 mg QD, though 200 mg BID was used in later studies. A Ph.
II study (FenOPTA, NCT05119569) in MS recently showed the drug reduces the number of
new gadolinium-enhancing T1 brain lesions and significantly reduce new or enlarging T2
brain lesions. The human half-life is 4.9-6.0 hours at 60-250 mg BID. Across clinical trials
including more than 2,500 people as of Oct. 2023, rates of adverse events were 38% with
fenebrutinib and 33% with placebo, with the most common differential adverse events being
abnormal liver enzyme levels (5.5% for fenebrutinib vs. 0% for placebo), headache (4.1% vs.
2.8%), nasopharyngitis (2.7% vs. 0%), and upper abdominal pain (2.7% vs. 0%).

Is Fenebrutinib Brain-Penetrant?
In a ACTRIMS 2022 presentation, Sanofi shared preclinical CNS pharmacology for various
BTK inhibitors evaluated in MS, including fenebrutinib, suggesting significant CNS
penetration. The following properties were reported:

• Fenebrutinib: Kp,uu (CSF, day 4, 10 mpk in NHPs): 0.147, 12.9 ng/mL Cmax; MPO score =
3.5, ~8 h CSF IC50 coverage, no IC90 coverage
• Tolebrutinib: Kp,uu (CSF, day 4, 10 mpk in NHPs): 0.397, 4.8 ng/mL Cmax; MPO score =
4.7, ~3 h IC90 coverage

More recently, in October 2023, Genentech reported CSF concentrations of fenebrutinib in 11

patients with RMS (data reported at ECTRIMS-ACTRIMS). After 12 weeks, mean fenebrutinib
concentration was 43.1 ng/mL (65 nM), which Genentech says correlates with near-maximal
(IC90) inhibition preclinically.

Given the long residence time of fenebrutinib, it is plausible that in humans, fenebrutinib
sufficiently engages BTK in the CNS for pharmacological activity in the CNS compartment,
though the data suggests that it is likely that future inhibitors can improve upon the total
dose required to achieve optimal target coverages in the CNS.

What’s Next?
Genentech is recruiting for two Ph. III clinical trials to compare fenebrutinib to teriflunomide
in patients with RMS (relapsing multiple sclerosis) and PPMS (primary-progressive multiple
sclerosis) (NCT04586023, NCT04586010) at 200 mg BID, with estimated completion dates
into 2026. The safety profile of fenebrutinib has remained consistent with its profile in
previous and ongoing clinical trials involving over 2,400 people, and no new safety concerns
were identified. The results of these studies suggest fenebrutinib may soon be evaluated for

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 other autoimmune indications. Fenebrutinib’s positive clinical signal is likely to trigger more
effort into reversible BTK inhibitors outside of oncology, as well as in alternative modalities
for targeting BTK like targeted protein degradation.

A Missed Opportunity In Oncology

It is notable that the Genentech team identified an opportunity to address drug resistance
in hematological cancers thanks to its reversible mode of action, demonstrating proof of
concept to this end in a 2018 paper. The work was done around the same time the first
approved reversible BTK inhibitor, pirtobrutinib, was given up by Redx Pharma to Loxo in
2017. Given the ultimate success of pirtobrutinib in oncology, it is not clear why Genentech
did not pursue fenebrutinib or related molecules in oncology given its strong preclinical data,
though one can speculate that as a larger commercial organization, it chose to prioritize
indications with larger potential commercial impact.

Lessons Learned
Fenebrutinib provides a valuable case study highlighting the potential safety advantages
of reversible inhibitors outside of oncology, how to deal with various forms of preclinical
toxicology, how drug-receptor residence time can impart covalent-like properties, how
the selection of a selective starting point can make a tremendous downstream impact, and
how a molecule of high quality against a target with myriad applications can lead to an
opportunity for success outside of an initially intended indication. The medicinal chemistry
campaign also highlights how small, single heavy-atom changes can lead to remarkable
pharmacological improvements with respect to PK, residence time, safety, and beyond.

Synthesis Highlights
The initial medicinal chemistry route to fenebrutinib and its precursors was highly
convergent allowing the route for process development to remain similar. One notable route
modification in a process route was in the synthesis of the tricyclic lactam intermediate
on the left side of the molecule. The medicinal chemists performed a Wittig olefination
extension of chlorovinyl aldehyde to yield the intermediate in 5 steps and 8% overall yield.
In process development, this route was replaced with a 1,4-aza-Michael addition and
cyclization of oxo-piperazine affording 51% yield in 1 step from the same starting material
to give the desired tricyclic lactam product on a >300kg scale. The tricyclic lactam was
then C-N coupled with the 2,4-dichloronicotinaldehyde in 95% yield. The right half of the
molecule was synthesized from chiral starting material (S)-2-methylpiperazine in 7 steps in
39% yield to provide the borylated Intermediate. These two halves were then coupled using a
Suzuki coupling and subsequently reduced to yield the final product in 70% over 2 steps.

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 Overall, the route was not greatly changed but the reactions were optimized and scaled to
provide a process for synthesizing fenebrutinib on a hundred kg scale.

O
Routes to Fenebrutinib: N
O
N
N
N NH N
O
O
N NH
Cl C-N coupling N HO
Cl N O Bpin N O
N +
NH N 85% yield N Cl N N
Suzuki Coupling
O O N and Reduction O N
2 steps, 70% yield

CO2Et
(Ph3)P
4 steps
Med. Chem. Route: Cl Cl N 5 steps, 8% overall yield
Wittig olefination NH
CHO
CO2Et O

HN
NH

Cl O
Process Route: N
1 step, 51% overall yield
CHO base-mediated NH
annulation
O

Relevant Patents
Heteroaryl pyridone and aza-pyridone compounds (USRE48239E1). Therapeutic compounds
and compositions, and methods of use thereof (US10307426B2). Dosage form compositions
comprising an inhibitor of bruton’s tyrosine kinase (US10246461B2).

10/15/23 Update:
Introduction and brain-penetration sections updated to include human CSF data reported by
Genentech at the 9th Joint ECTRIMS-ACTRIMS meeting.

6/6/24 Update:
Fenebrutinib was placed on a partial clinical hold by the FDA in Dec. 2023. The decision was
made based on two recent cases of suggesting potential DILI risk, characterized by elevation
of hepatic transaminases in conjunction with elevated bilirubin levels during the blinded Ph.
III trials in relapsing MS. Both patients were asymptomatic and bilirubin as well as ALT/AST
levels returned to normal after drug discontinuation. As a result, enrollment in the US was
paused but continued outside of the US. Patients who received fenebrutinib 70 days or longer

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 in the US are continuing the trial. Only a small number of patients who received fenebrutinib
70 days or less discontinued treatment. Fenebrutinib remains in Genentech’s development
pipeline as of Jun. 6, 2024. It is possible that the FDA’s caution was heightened with FDA
clinical holds of several BTK inhibitors including orelabrutinib (Biogen, Ph. II, 2022),
tolebrutinib (Sanofi, Ph. III, 2022), evobrutinib (Merck KGaA, Ph. III, 2023). The pattern is
similar in all cases (reversible lab-based observations).

In Mar. 2024 Merck KGaA announced that they will discontinue development of evobrutinib
for the treatment of MS. The decision was made based on the non-superiority of evobrutinib
compared to Sanofi’s DHODH (dihydroorotate dehydrogenase) inhibitor teriflunomide.

BTK appears to remain an actively pursued target for MS. Biogen just disclosed the discovery
campaign of their covalent BTK inhibitor BIIB129, which is a Molecule of the Month in May
2024, and has a peripheral BTK inhibitor listed in its pipeline for MS in Ph. II as of Jun. 6,
2024 (BIIB091).

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