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Item 1. Business

2024-03-20 compared with 2023-03-22 · 349 added, 423 removed, 409 unchanged (65% of the section changed)

We are a clinical stage biotherapeutics company focusing on advancing technologies to enable the administration of biologics and drugs orally, to provide patients, physicians, and healthcare systems with a convenient alternative to painful injections.

We are advancing a portfolio of oral therapeutics using our proprietary delivery technology.

We are developing and clinically testing a drug-agnostic oral delivery platform, the RaniPill capsule, which is designed to deliver a wide variety of drug substances, including large molecules such as peptides, proteins, and antibodies.

The current RaniPill capsule, the RaniPill GO, is designed to deliver up to a 3 mg dose of drug with high bioavailability.

We are also developing a high-capacity version known as the RaniPill HC, which is in preclinical stage and which is intended to enable delivery of drug payloads up to 20 mg with high bioavailability.

The RaniPill GO is optimized to orally deliver a variety of therapeutics, and we are advancing development of the RaniPill HC to address biologics and drugs with higher dosing requirements.

We believe that, together, the RaniPill GO and RaniPill HC could enable us to deliver most biologics currently on the market via a convenient, oral daily dose.

We are advancing a portfolio of oral therapeutics using our proprietary delivery technology and we are actively pursuing partnering the technology with third party biopharmaceutical companies for the oral delivery of their biologics and drugs.

Our technology comprises a drug-agnostic oral delivery platform, the RaniPill capsule, which is designed to deliver a wide variety of drug substances, including antibodies, proteins, peptides, and oligonucleotides.

We are currently developing two configurations of the platform – the RaniPill GO and the RaniPill HC.

The RaniPill GO is designed to deliver up to a 3 mg dose of drug in microtablet form with high bioavailability.

We have completed three Phase 1 clinical trials using the RaniPill GO.

We are also developing a high-capacity version of the RaniPill capsule known as the RaniPill HC, which is intended to enable delivery of drug payloads up to 200µL in liquid form with high bioavailability.

We have tested preclinically the RaniPill HC with multiple therapeutics, including antibodies and a peptide.

We intend to initiate clinical testing of the RaniPill HC in the second half of 2024.

We believe that, together, the RaniPill GO and RaniPill HC could enable us to deliver most biologics currently on the market with convenient, oral dosing.

Data Overview

We have completed two Phase 1 clinical trials with the RaniPill capsule technology.

In 2022, we completed a Phase 1 clinical trial with RT-102, a RaniPill GO capsule containing our proprietary formulation of parathyroid hormone (1-34) (“PTH”), in Australia.

We have completed three Phase 1 clinical trials with the RaniPill capsule technology.

In February 2024, we announced completion of a Phase 1 clinical trial with RT-111, a RaniPill GO capsule containing our proprietary formulation of an ustekinumab biosimilar supplied by Celltrion, Inc.

(“Celltrion”), in Australia.

The study evaluated the safety and tolerability of a single administration of RT-111 in healthy adult volunteers.

The study met all its endpoints, RT-111 was well tolerated and delivered ustekinumab biosimilar with high bioavailability.

No serious adverse events were reported in the study.

In 2022, we completed a Phase 1 clinical trial with RT-102, a RaniPill GO capsule containing our proprietary formulation of parathyroid hormone (1-34) (“PTH”), in Australia.

The study involved a single-ascending dose portion and a seven-day repeat-dose portion.

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In our clinical studies, our product candidates were generally well tolerated and no serious adverse events were observed.

Preclinically, we have tested 12 molecules in the RaniPill capsule, including five antibodies, six peptides and one large protein.

We have conducted preclinical testing of more than 1,700 RaniPill capsules in vitro and more than 1,300 RaniPill capsules in vivo, including two good laboratory practice (“GLP”) seven-day repeat-dose studies which supported advancement of our product candidates, RT-101 and RT-102, into clinical studies.

Preclinically, we have tested 15 molecules in the RaniPill capsule, including eight antibodies, six peptides and one large protein.

We have conducted preclinical testing of more than 7,000 RaniPill capsules in vivo and in vitro.

In October 2023, we announced preclinical data from a 60-day, repeat oral-administration good laboratory practices (“GLP”) safety study of the RaniPill capsule in healthy animals.

The RaniPill capsule was well tolerated with no treatment-related adverse events and all animals remained clinically healthy throughout the study.

As of January 1, 2024, we had tested more than 200 RaniPill HC devices in vivo including delivery of a peptide and multiple different antibodies.

The RaniPill HC represents a significant opportunity to potentially enable the oral delivery of more than ninety additional biologics currently on the market, including therapeutics like dupilumab, secukinumab, pembrolizumab, etanercept and trastuzumab.

We intend for the RaniPill HC to be ready for potential Phase 1 clinical trials in the second half of 2024.

Business Update

In November 2023, we announced a strategic program prioritization, expansion of manufacturing and plans to streamline business operations to support near-term value drivers and long-term growth of the RaniPill technology platform (the “Restructuring”).

The plans include strategic prioritization of its key development programs, RT-102, RT-111 and the RaniPill HC and expansion of our manufacturing footprint to support increased scale and partnerships, and cost reduction initiatives that align with our near-term goals, including a reduction in our workforce by approximately 25%.

As part of the strategic focusing of the business, we have paused work on our RT-105 and RT-110 programs and we terminated our RT-101 program, which was the RaniPill capsule containing octreotide.

Pipeline Overview

The broad utility of the RaniPill capsule to enable the oral delivery of biologics provides us with a range of attractive development opportunities.

The broad utility of the RaniPill capsule to enable the oral delivery of biologics and drugs provides us with a range of attractive development opportunities.

We have prioritized development based on specific scientific, developmental, regulatory, and commercial considerations to optimize our portfolio of targeted product candidates.

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* Clinical timelines are subject to potential regulatory agency review delays.

** Each of these indications will require separate regulatory approvals.

** Partnered with Celltrion, Inc.

Celltrion, Inc.

supplies ustekinumab pursuant to a license and supply agreement and has a right of first negotiation for development and commercial rights following completion of a Phase 1 clinical trial that meets its primary endpoint(s).

Clinical Update

In August 2022, we announced positive topline results from Part 1 (“Study Part 1”) of the Phase 1 study of RT-102, which is being developed for the potential treatment of osteoporosis.

The study met all of its endpoints and RT-102 was generally well tolerated.

In the study, RT-102 orally delivered 20 µg and 80 µg of PTH with 300-400% greater bioavailability than subcutaneous Forteo (teriparatide) 20 µg.

In December 2022, we announced positive topline results from Part 2 (“Study Part 2”) of the Phase 1 study of RT-102.

The study met all of its endpoints.

The study evaluated the safety and tolerability of once-daily administration of RT-102 containing 20 µg of PTH given repeatedly for seven consecutive days in ten healthy female volunteers.

RT-102 was well tolerated with no serious adverse events noted, and delivered 20 µg of PTH with high bioavailability, confirming the high bioavailability observed in Study Part 1.

supplies the drug pursuant to a license and supply agreement and has a right of first negotiation for development and commercial rights following completion of a Phase 1 clinical trial that meets its primary endpoint(s).

Our Pipeline Programs

Ustekinumab for the treatment of inflammatory conditions

Market overview

Ustekinumab is currently approved by the FDA and European Medicines Agency (“EMA”) for the treatment of various inflammatory conditions under the brand name STELARA.

STELARA (ustekinumab) is an interleukin-12 and interleukin-23 antagonist marketed by Janssen Biotech, Inc.

with sales of approximately $6.4 billion in the United States and approximately $9.7 billion worldwide in 2022.

The latest expiring United States patent for STELARA (ustekinumab) expired in 2023.

In the United States, there were estimated to be seven million patients with psoriasis and three million patients with Crohn’s disease or ulcerative colitis in 2021.

Our solution:

We are developing RT-111, a RaniPill capsule containing an ustekinumab biosimilar, for the treatment of various inflammatory conditions.

We entered into a License and Supply Agreement with Celltrion, under which we receive a license and supply of Celltrion’s ustekinumab biosimilar for development and commercialization worldwide, subject to a right of first negotiation for Celltrion following completion of a Phase 1 clinical trial that meets its primary endpoint(s).

Clinical trials

In February 2024, we announced positive topline results from a Phase 1 study of RT-111, which is being developed for the potential treatment of inflammatory conditions.

The study met all of its endpoints and RT-111 was generally well tolerated with no serious adverse events noted.

In the study, RT-111 orally delivered 0.5 mg and 0.75 mg of our proprietary formulation of ustekinumab biosimilar with high bioavailability.

The single-center, open label Phase 1 study of RT-111 was conducted in Australia.

The study evaluated the safety, and tolerability of a single administration of RT-111 in healthy adult volunteers.

Of the 55 participants, 20 orally ingested RT-111 containing a single 0.5 mg dose of ustekinumab biosimilar and 20 orally ingested RT-111 containing a single 0.75 mg dose of ustekinumab biosimilar, while a control group of 15 participants received a single 0.5 mg subcutaneous injection of STELARA, a commercial formulation of ustekinumab for subcutaneous (“SC”) administration.

In the Phase 1 study, RT-111 was generally well tolerated, with no serious adverse events (“SAE”) noted during the study.

None of the participants withdrew from the study due to any adverse event.

Two subjects in the 0.5mg RT-111 group and one subject in the 0.5mg SC STELARA® group had mild, transient adverse events which resolved without any intervention.

There was no meaningful difference in incidence of anti-drug antibodies via the RaniPill route of delivery compared to STELARA® SC injection.

Stelara® SC 0.50 mg

RT-111 0.50 mg

RT-111 0.75 mg

Drug Signal Detected

Number of ADA Positive Cases

Total ADA Positive*

* ADA positive post dosing, increase in titer compared to pre-dose level

No participants reported difficulty swallowing the capsule and capsule remnants passed from all participants without sequelae.

Pharmacokinetics (“PK”)

• Oral RT-111 delivered 0.5mg and 0.75mg of ustekinumab biosimilar with high bioavailability (estimated bioavailability of 84% for 0.5mg RT-111 relative to 0.5mg SC STELARA®).

Stelara ® SC 0.50mg

RT-111 0.50mg

RT-111 0.75mg

AUC (day*ng/mL)

Bioavailability

Data are Mean ± SE from all subjects, including those with anti-drug antibodies.

*p<0.0001 significantly different from SC group.

License and Supply Agreement

In January 2023, we announced entering into a License and Supply Agreement with Celltrion under which we receive a license and supply of Celltrion’s ustekinumab biosimilar for development and commercialization of RT-111 worldwide, subject to a right of first negotiation for Celltrion following completion of a Phase 1 clinical trial that meets its primary endpoint(s).

We believe the Phase 1 clinical trial that we completed with RT-111, the topline data of which we announced in February 2024, satisfies the requirements for triggering Celltrion’s right of first negotiation.

We intend to advance clinical development of RT-111 at higher doses.

Parathyroid hormone (PTH) for the treatment of osteoporosis

Market overview

Osteoporosis is a bone disease where bone mineral density and bone mass decreases, leading to a decrease in bone strength that can increase the risk of fractures.

Osteoporosis affects women and men of all races and ethnic groups.

Osteoporosis can occur at any age, although the risk for developing the disease increases with age.

PTH is an effective bone-building treatment for osteoporosis.

PTH is a hormone secreted by the parathyroid glands that regulates serum calcium concentration and promotes bone growth.

PTH therapies are delivered by daily subcutaneous injections for up to two years.

Approximately ten million Americans suffer from osteoporosis;

however, we estimate that only a small fraction of this population is being treated with a form of PTH.

While there may be other reasons for this, we believe that patient aversion to daily injections may be a major factor.

As a result, non-bone-building and less effective antiresorptive drugs are used as first line therapies because they are available in oral form.

Teriparatide, a synthetic form of the natural human parathyroid hormone hPTH(1-34), is a PTH analog administered as a once-daily injection to treat osteoporosis, first developed by Eli Lilly and Company and sold under the brand name Forteo.

Another PTH analog injectable is Tymlos by Radius Health, Inc., which was approved in 2017.

A teriparatide biosimilar injectable by Pfenex, Inc.

was approved in 2019.

Annual sales revenue of PTH analogs and biosimilars globally in 2021 was approximately $2.0 billion.

Our solution:

We are developing RT-102, the RaniPill capsule containing our novel formulation of PTH, for oral treatment of osteoporosis.

We have worldwide commercial rights to RT-102.

In addition to the existing market, we believe there is an opportunity to expand the market by advancing RT-102 as a first line therapy for osteoporosis.

Preclinical pharmacodynamic study

We conducted a 6-week pharmacodynamic study of the RT-102 drug substance PTH (1-34) to evaluate the effect of daily RT-102 drug substance (“DS”) intraperitoneal injections on bone mineral density in a rodent model of osteoporosis.

The study compared two control groups of rodents undergoing sham surgery (N=10) and ovariectomy (N=10) receiving no drug, to three overiectomized groups each dosed with 5 mcg/kg per day of either RT-102 DS (N=10), teriparatide (N=10), or abaloparatide (N=10).

The study found that, following six weeks of treatment:

• RT-102 DS increased bone mineral density (“BMD”) in a rat model of osteoporosis.

• RT-102 DS delivered via the intraperitoneal (“IP”) route of administration was biologically active comparable to subcutaneously injected PTH analogs.

Clinical trials

In 2022, we completed a Phase 1 clinical trial with RT-102 in Australia.

The study involved a single-ascending dose portion (“Study Part 1”) and a seven-day repeat-dose portion (“Study Part 2”).

The Phase 1 study met all of its endpoints, RT-102 was well tolerated and delivery yielded high bioavailability (more than 300% greater bioavailability than subcutaneous injection).

No serious adverse events were reported in the study.

We plan to initiate a Phase 2 clinical trial of RT-102 in 2024.

Study Part 1 - Topline Results

The single-center, open label, Study Part 1 was conducted in Australia.

The study evaluated the safety, tolerability, and pharmacokinetics (“PK”) of RT-102 in healthy adult female volunteers.

Of the 39 participants, 15 were administered RT-102 containing a single 20 μg dose of PTH and 14 were administered RT-102 containing a single 80 μg dose of PTH, while a control group of ten participants received a single 20 μg subcutaneous injection (SC) of Forteo (teriparatide), a commercial formulation of PTH for subcutaneous (“SC”) administration.

The study evaluated the safety, tolerability, and pharmacokinetics of RT-102 in healthy adult female volunteers.

The endpoints of the study were safety and tolerability, and measurements of serum concentrations of RT-102 in healthy adult female volunteers.

In Study Part 1, RT-102 was generally well tolerated, with no RaniPill-related adverse events (“AEs”) observed in study participants:

o 0% (0/15) of participants dosed with RT-102 20 μg experienced drug-related AEs.

o 14% (2/14) of participants dosed with of RT-102 80 μg experienced drug-related AEs.

o 50% (5/10) of participants dosed with 20 μg of Forteo SC experienced drug-related AEs.

o There were no serious adverse events (“SAEs”) noted during Study Part 1.

• In Study Part 1, RT-102 was generally well tolerated, with no RaniPill-related adverse events (“AEs”) observed in study participants:

• 0% (0/15) of participants dosed with RT-102 20 μg experienced drug-related AEs.

• 14% (2/14) of participants dosed with of RT-102 80 μg experienced drug-related AEs.

• 50% (5/10) of participants dosed with 20 μg of Forteo SC experienced drug-related AEs.

• There were no serious adverse events (“SAEs”) noted during Study Part 1.

Per protocol, in instances where the RaniPill capsule did not exit the stomach within seven hours, participants were excluded from the study.

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Pharmacokinetics

In Study Part 1, RT-102 (20 μg and 80 μg) orally delivered PTH with 300%-400% greater bioavailability than PTH delivered by Forteo SC (20 μg).

RT-102 20 μg delivered PTH with lower, more sustained peak serum levels and higher area under the curve (“AUC”) than Forteo SC 20 μg.

Forteo SC 20 μg

RT-102 20 μg

RT-102 80 μg

• In Study Part 1, RT-102 (20 μg and 80 μg) orally delivered PTH with 300%-400% greater bioavailability than PTH delivered by Forteo SC (20 μg).

• RT-102 20 μg delivered PTH with lower, more sustained peak serum levels and higher area under the curve (“AUC”) than Forteo SC 20 μg.

Forteo SC 20 μg

AUC (h*pg/mL)

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• Two versions of the RaniPill capsule were used during Study Part 1:

Version C, which was used in Rani’s prior Phase 1 study of octreotide (which also utilized a Version A and Version B);

Version C, which was used in our prior Phase 1 study of octreotide (which also utilized a Version A and Version B);

and Version D, the latest iteration of the RaniPill capsule.

• RaniPill Version D demonstrated a higher drug delivery success rate than Version C:

95% (20/21) of participants received successful drug delivery when ingesting RaniPill Version D.

75% (6/8) of participants received successful drug delivery when ingesting RaniPill Version C.

o 95% (20/21) of participants received successful drug delivery when ingesting RaniPill Version D.

o 75% (6/8) of participants received successful drug delivery when ingesting RaniPill Version C.

The device performance analysis does not include participants excluded from the study per protocol, as drug delivery was not measured in such participants.

Study Part 2 - Topline Results

Study Part 2 was a continuation of Rani’s single-center, open-label Phase 1 study of RT-102 conducted in Australia.

The study evaluated the safety and tolerability of once-daily administration of RT-102 containing 20 μg of PTH given repeatedly for seven consecutive days in ten healthy female volunteers (five of whom were post-menopausal).

Study Part 2 was a continuation of Rani’s single-center, open-label Phase 1 study of RT-102 conducted in Australia.

Complete pharmacokinetic profiles of PTH were obtained for each subject on Day 7.

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Pharmacokinetics

RT-102 delivered 20 µg of PTH with high bioavailability (relative to 20 µg SC Forteo (teriparatide) in Study Part 1), confirming the high bioavailability of PTH delivered via the RaniPill capsule observed during Study Part 1.

• RT-102 delivered 20 µg of PTH with high bioavailability (relative to 20 µg SC Forteo (teriparatide) in Study Part 1, confirming the high bioavailability of PTH delivered via the RaniPill capsule observed during Study Part 1.

Device Performance

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The number of successful deployments was comparable before and after food was consumed.

In January 2023, Rani announced that it completed a pre-IND meeting with the FDA with respect to RT-102.

Following feedback from the meeting, Rani believes that a 505(b)(2) pathway is suitable for the development of RT-102 in the U.S.

In addition, Rani obtained guidance from the FDA on its preclinical and clinical development plans for RT-102, including the Phase 2 clinical trial which is expected to initiate in the second half of 2023.

Pharmacodynamics - Rodent Study

We also conducted a 6-week pharmacodynamic (“PD”) study of the RT-102 drug substance (“DS”) PTH (1-34) to evaluate the effect of daily RT-102 DS intraperitoneal (“IP”) injections on bone mineral density (“BMD”) in a rodent model of osteoporosis.

The study compared two control groups of rodents undergoing sham surgery (N=10) and ovariectomy (“OVX”) (N=10) receiving no drug, to three OVX groups each dosed with 5 mcg/kg per day of either RT-102 DS (N=10), teriparatide (N=10), or abaloparatide (N=10).

The study found that, following six weeks of treatment:

RT-102 DS increased BMD in a rat model of osteoporosis.

RT-102 DS delivered via the IP route of administration was biologically active comparable to SC injected PTH analogs.

In October 2022, we announced that we had begun preclinical development with RT-111, the RaniPill capsule containing an ustekinumab biosimilar.

In January 2023, we announced entering into a License and Supply Agreement with Celltrion, Inc.

(“Celltrion”) under which we receive a license and supply of Celltrion’s ustekinumab biosimilar for development and commercialization of RT-111 worldwide, subject to a right of first negotiation for Celltrion following completion of a Phase 1 clinical trial that meets its primary endpoint(s) (the “Celltrion Agreement”).

We continue to develop the RaniPill HC, a high-capacity RaniPill capsule designed to deliver drug payloads up to 20 mg, 500%-plus higher than the payload capacity of the RaniPill GO.

We are conducting preclinical studies with a fully-autonomous RaniPill HC.

Following a strategic priority review in 2022, we decided not to continue active development of RT-109, a RaniPill capsule containing human growth hormone.

We remain open to partnering opportunities with respect to RT-109, but intend to focus internal efforts on our other pipeline programs.

We have completed a pre-IND meeting with the FDA with respect to RT-102.

Following feedback from the meeting, we believe that a 505(b)(2) pathway is suitable for the development of RT-102 in the U.S.

In addition, we obtained guidance from the FDA on our preclinical and clinical development plans for RT-102.

We intend to initiate a Phase 2 clinical trial of RT-102 in 2024.

Anti-TNF-alpha antibody for the treatment of psoriatic arthritis

Market overview

Anti-TNF-alpha antibodies such as adalimumab are used to treat a range of inflammatory disorders and are among the largest selling class of pharmaceutical drugs globally as measured by revenue.

Adalimumab, sold by AbbVie Inc.

under the brand name Humira, generated sales of approximately $21.2 billion in 2022.

Adalimumab is approved by the FDA and EMA to treat a range of autoimmune conditions, including psoriasis, rheumatoid arthritis, and Crohn’s disease.

alone, there are an estimated one and one-half million patients with rheumatoid arthritis, seven million with psoriasis, and three million with Crohn’s disease or ulcerative colitis.

At least eight Humira biosimilars entered the U.S.

market over the course of 2023.

Patients who use adalimumab administer the drug through a subcutaneous injection once every two weeks.

Despite the painful injections required to administer it, adalimumab was the best-selling drug globally in 2020.

Our solution:

We are developing RT-105, the RaniPill capsule containing a formulation of adalimumab, for oral treatment of a host of inflammatory conditions, beginning with treatment of psoriatic arthritis and later expanding to other indications for which TNF-alpha inhibitors are approved.

We believe that the development of an orally administered anti-TNF-alpha antibody represents a significant market opportunity.

In June 2023, we entered into a License and Supply Agreement with Celltrion under which we receive an exclusive license and supply of Celltrion’s adalimumab biosimilar for development and commercialization of RT-105 worldwide, subject to a right of first negotiation for Celltrion.

Preclinical studies

We evaluated the performance of RT-105 containing an adalimumab biosimilar in awake canines and compared it to the performance of the adalimumab biosimilar given by way of subcutaneous and intravenous injection.

The PK profile for RT-105 was comparable to the profile for subcutaneous administration, and mean bioavailability for RT-105 was 49%, compared to 46% with subcutaneous injection.

Clinical trials

Endoscopic administration of adalimumab into the jejunum of healthy human volunteers

To assess whether the observations from preclinical studies regarding absorption of adalimumab through the intestinal wall translate to clinical trials, we conducted an endoscopic study in humans.

The study involved ten healthy volunteers and compared the PK of an approved formulation of adalimumab injected endoscopically into the jejunal intestinal wall, which mimics the RaniPill capsule route of administration, to that of an identical dose injected subcutaneously.

Blood samples were obtained at prescribed intervals during a 14-day study period.

PK profiles were similar with no notable differences observed in either area under the curve (“AUC”) or maximum serum concentration (“Cmax”).

The mean AUC was 62.7 ± 11.4 µg/ml*day*kg/mg for the subcutaneous group and 45.0 ± 29.0 µg/ml*day*kg/mg for the intrajejunal group.

No serious adverse events were noted in this study, and adverse events of headache and flu-like symptoms after intrajejunal administration resolved within 48 hours.

The results are consistent with data obtained in preclinical studies, confirming intrajejunal delivery as a viable route of delivery for adalimumab.

In November 2023, we announced the pausing of development of RT-105 as part of a strategic focusing of the business.

The next milestone for this program will be to initiate a Phase 1 clinical trial of RT-105.

Under the Celltrion Agreement for adalimumab, Celltrion will have a right to terminate the agreement if we do not initiate a Phase 1 clinical trial with RT-105, or fail to deliver to Celltrion topline data from a Phase 1 trial that meets its primary endpoint(s), within certain agreed time periods.

We anticipate resuming this program in time to enable us to satisfy these requirements.

PTH for the treatment of hypoparathyroidism

Market overview

Hypoparathyroidism is a rare condition of low levels of serum PTH resulting in low calcium levels in the blood.

The prevalence of hypoparathyroidism in the United States is approximately 115,000 people.

PTH is currently approved for the treatment of hypoparathyroidism by the FDA and EMA.

PTH treatment requires lifelong daily injections but has suboptimal efficacy.

Treatment of hypoparathyroidism is most effective with consistent and sustained plasma levels of PTH.

Our solution:

We are developing RT-110, the RaniPill capsule containing our second novel formulation of PTH, for oral treatment of hypoparathyroidism.

We are creating a sustained release formulation of RT-110 which is intended to provide continuous exposures of the hormone required to normalize the calcium imbalance in hypoparathyroidism patients.

We have worldwide commercial rights to RT-110.

We believe that there is an unmet need for a delivery method more convenient than injection, and we further believe that the RaniPill capsule could provide for a treatment regimen that can better maintain consistent and sustained plasma levels of PTH than the current treatment regimen of daily PTH injections.

In November 2023, we announced the pausing of development of RT-110 as part of a strategic focusing of the business.

The next milestone for this program would be to initiate a Phase 1 clinical trial in healthy volunteers.

The Market and Our Strategy

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Biologics include, for example, recombinant therapeutic proteins, peptides, and monoclonal antibodies, as well as cell and gene therapies.

In 2020, worldwide sales of biologics were estimated to have reached approximately $253.4 billion and are projected to reach $420.6 billion by 2025.

The global biologics market size is estimated to be $429.5 billion in 2024 and is expected to reach $601.26 billion by 2029.

Biologics must generally be administered through intravenous, intramuscular, or subcutaneous injection.

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Bioavailability refers to the proportion of a delivered dose that reaches the bloodstream in active form.

Attempts at oral delivery of biotherapeutics have remained largely unsuccessful due to the rapid degradation and digestion of biologics in the gastrointestinal (“GI”) environment before they can be absorbed into the bloodstream.

Our solution is a novel, proprietary and patented platform technology referred to as the RaniPill capsule, an orally ingestible pill designed to automatically deploy in the small intestine to administer a precise therapeutic dose of a biologic into the intestinal wall.

Our several preclinical studies and clinical trials have demonstrated bioavailability of biologics dosed via the RaniPill capsule that is generally comparable to the bioavailability of biologics dosed subcutaneously, with high dosing accuracy:

this level of bioavailability is significantly higher than any that has been demonstrated with respect to others’

attempts at oral delivery of biologics.

this level of bioavailability is significantly higher than any that has been demonstrated with respect to others’ attempts at oral delivery of biologics.

We are pursuing a number of clinical and preclinical pipeline programs utilizing our RaniPill capsule.

In addition, our newly designed high-capacity oral biologic delivery device, the RaniPill HC, has the potential to deliver 500%-plus higher payloads than our current RaniPill GO capsule.

We believe this is a significant breakthrough in drug delivery with the potential to provide expansive opportunities for the company, such that we could potentially pursue a daily dosing option for over 50 additional biologics, for internal development or through partnership, including such biologics as pembrolizumab, etanercept, trastuzumab and secukinumab.

We believe this is a significant breakthrough in drug delivery with the potential to provide expansive opportunities for the company, such that we could potentially pursue a convenient dosing option for over 50 additional biologics, for internal development or through partnership, including such biologics as dupilumab, pembrolizumab, etanercept, trastuzumab and secukinumab.

We believe that oral biologics utilizing our RaniPill technology have the potential to disrupt the large and growing biologics market.

Our strategic vision is to disrupt and expand the market currently served by injectable only therapeutic biologics.

We plan to do this by developing and advancing oral biologics therapies, directly ourselves and through partnering.

We plan to do this by developing and advancing a pipeline of oral biologics therapies to unlock the value of these assets and to progress platform development and by actively pursuing partnering of the technology with third party biopharmaceutical companies for the oral delivery of their biologics and drugs.

We also intend to explore opportunities to demonstrate the potential of the delivery platform in additional modalities and therapeutics areas.

We believe that the RaniPill capsule has the potential to improve the lives of millions of patients with chronic diseases who currently depend on biologics and drugs available only as injections.

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• Pursue validated and commercially established market opportunities.

We intend to pursue high-value markets with biologics that are already approved where we can develop our own differentiated products.

We intend to pursue high-value markets with biologics that are already approved or validated where we can develop differentiated products.

We believe that these products will take market share from available therapies, while also expanding existing markets by reaching new patient populations that otherwise are not being treated by injectable biologics.

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We have vertically integrated our manufacturing, and plan to continue to scale and optimize our manufacturing processes by expanding our use of automation.

For commercial scale manufacturing, we will consider engaging one or more third party contract manufacturers,

• Invest in RaniPill capsule capabilities.

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• Expand our reach by selectively entering into strategic partnerships.

We are opportunistically exploring strategic partnerships to enable us to expand our commercial reach and enable oral administration of a broader array of biologics.

We are actively exploring strategic partnerships to enable us to expand our commercial reach and enable oral administration of a broader array of biologics and drugs.

• Continue to strengthen our intellectual property portfolio.

Our patent portfolio has helped establish us as a leading oral biologics company.

We plan to continue to innovate and expand our intellectual property by developing novel formulations and new applications of the RaniPill capsule.

We plan to continue to innovate and expand our intellectual property by developing further innovations and new applications of the RaniPill capsule.

Rani LLC was founded by Mir Imran, our Chairman of the Board, who continues to contribute to our strategic planning and product development.

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Our Platform Technology

We are currently developing two configurations of the platform – the RaniPill GO and the RaniPill HC.

The RaniPill GO is designed to deliver up to a 3 mg dose of drug in microtablet form with high bioavailability.We are also developing a high-capacity version of the RaniPill capsule known as the RaniPill HC, which is intended to enable delivery of drug payloads up to 200µL in liquid form with high bioavailability.

Each of our product candidates is a RaniPill capsule containing a biologic.

We may use the term RaniPill platform herein to refer to the physical structure and/or mechanisms of the RaniPill capsule absent a biologic.

Our clinically tested RaniPill delivery platform described below is intended to be capable of delivering up to a 3 mg dose of any drug.

We are also developing a high-capacity version known as the RaniPill HC, and which is intended to enable delivery of drug payloads up to 20 mg and is in preclinical testing stage.

We may use the term RaniPill platform or RaniPill device herein to refer to the physical structure and/or mechanisms of the RaniPill capsule absent a biologic.

The RaniPill capsule

The RaniPill capsule is a versatile, drug-agnostic, orally ingestible pill approximately the size of a fish oil or calcium pill or a ‘000’-sized capsule.

RaniPill capsule in purple next to fish oil pills (gold) and calcium pills (white).

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The balloon immediately deflates upon microneedle delivery and is excreted through normal digestive processes.

The RaniPill HC operates similar to the RaniPill GO except that, instead of delivering a dissolvable microneedle containing a solid microtablet of drug, the RaniPill HC uses a dissolvable needle to deliver the drug payload in liquid form.

Features and advantages of the RaniPill capsule

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Some of the features and advantages of the RaniPill capsule are listed below.

High bioavailability and high dosing accuracy –

Our studies conducted to date have demonstrated that the RaniPill capsule delivers biologics with bioavailability that is generally comparable to subcutaneous injection, with high dosing accuracy.

This level of bioavailability is similar to subcutaneous injection and is significantly higher than that of currently marketed chemistry-based oral biologics, the best attempts of which to our awareness have resulted in peptides being delivered with only low single-digit bioavailability.

Protective coating avoids deployment in the stomach –

The proprietary protective coating formulation is pH-sensitive, enabling the RaniPill capsule to maintain its integrity through the acidic environment in the stomach for deployment in the small intestine.

Protection of the drug prior to delivery –

The microneedle is protected from intestinal fluid until delivery, and then the rapid injection of the microneedle into the intestinal wall during delivery provides for little or no exposure of the microneedle to intestinal fluid.

This technique serves to overcome the body’s natural mechanisms that break biologics down in the harsh GI environment and thus block biologics from reaching the blood stream from within the intestine.

Proprietary microneedle design preserves drug integrity and sterility –

The proprietary dissolvable microneedle is made from injectable-grade, sterile materials.

The microneedle is designed to accommodate in its hollow interior a biologic formed into a microtablet of up to 3 mg.

Once exposed to body fluids, the microneedle begins to dissolve and expose the biologic for absorption into the vasculature.

The sealed microneedle preserves the integrity and sterility of the biologic until the microneedle dissolves.

Delivery of the microneedle in both fed and fasted states –

The RaniPill capsule is designed to deliver the microneedle even if the patient ingests the RaniPill capsule with or without food, which we expect will allow for more flexible dosing regimens and improved patient adherence to a given regimen.

Self-inflating balloon ensures reliable delivery –

The proprietary self-inflating balloon is designed to provide optimal pressure to deliver the microneedle.

In addition, the novel design of the balloon positions the microneedle approximately perpendicular to the intestinal wall for reliable drug delivery, with greater than 90% drug delivery success observed in our Phase 1 clinical trial of RT-102.

• High bioavailability and high dosing accuracy – Our studies conducted to date have demonstrated that the RaniPill capsule delivers biologics with high bioavailability and high dosing accuracy.

This level of bioavailability is significantly higher than that of currently marketed chemistry-based oral biologics, the best attempts of which to our awareness have resulted in peptides being delivered with only low single-digit bioavailability.

• Protective coating avoids deployment in the stomach – The proprietary protective coating formulation is pH-sensitive, enabling the RaniPill capsule to maintain its integrity through the acidic environment in the stomach for deployment in the small intestine.

• Protection of the drug prior to delivery – The microneedle and drug are protected from intestinal fluid until delivery, and then the rapid injection of the microneedle into the intestinal wall during delivery provides for little or no exposure of the microneedle or drug to intestinal fluid.

• Delivery in both fed and fasted states – The RaniPill capsule is designed to deliver the drug payload regardless of whether the patient ingests the RaniPill capsule with or without food, which we expect will allow for more flexible dosing regimens and improved patient adherence to a given regimen.

• Self-inflating balloon ensures reliable delivery – The proprietary self-inflating balloon is designed to provide optimal pressure to deliver the payload.

In addition, the novel design of the balloon positions the microneedle approximately perpendicular to the intestinal wall for reliable drug delivery, with greater than 90% cumulative drug delivery success observed with the latest version of the RaniPill capsule used in our Phase 1 clinical trials of RT-102 and RT-111.

The self-inflating balloon has been designed to minimize GI discomfort.

Drug-agnostic design provides a standardized platform –

The RaniPill capsule is designed to deliver any molecule irrespective of its molecular mass.

• Drug-agnostic design provides a standardized platform – The RaniPill capsule is designed to deliver any molecule irrespective of its molecular mass.

This allows a single platform design to be used with multiple drugs.

Optimized dosing regimen –

Based on the confirmed patient preference for oral delivery alternatives, we expect better treatment adherence with oral dosing versus injections, thus enabling a more physician-selectable dosing regimen.

For example, the RaniPill capsule may enable a regimen of small daily doses, versus larger less-frequent doses for injections, to improve treatment adherence.

In addition, small daily dosing may allow for therapeutic exposures to be maintained within a narrow range, whereas larger less frequent injection dosing can lead to large variations in therapeutic exposure, which can directly contribute to adverse events, loss of efficacy, and increased propensity for immunogenic response.

• Optimized dosing regimen – Based on the confirmed patient preference for oral delivery alternatives, we expect better treatment adherence with oral dosing versus injections, thus enabling a more clinically-favorable dosing regimen.

For example, the RaniPill capsule may enable a regimen of small, more frequent doses, versus larger less frequent doses for injections, to improve treatment adherence.

In addition, small, more frequent dosing may allow for therapeutic exposures to be maintained within a narrow range, whereas larger less frequent injection dosing can lead to large variations in therapeutic exposure, which may contribute to adverse events, loss of efficacy, and increased propensity for immunogenic response.

We continue to develop the RaniPill HC, a high-capacity RaniPill capsule designed to deliver drug payloads up to 200µL, 500%-plus higher than the payload capacity of the RaniPill GO.

In September 2023, we announced three positive preclinical studies which support the development of the RaniPill HC device.

Rani conducted two preclinical studies of the RaniPill HC containing 40ug of teriparatide.

In the first study, two RaniPill HC capsules were orally administered to 5 awake canine subjects sequentially, with a second RaniPill HC capsule administered after the deployment of the previous device was confirmed.

In the second study, a single RaniPill HC capsule was administered to ten awake canines.

• RaniPill HC achieved 18/20 successful drug delivery of teriparatide in the two studies, resulting in a cumulative 90% success rate.

• Successful drug delivery was confirmed by positive drug signal for teriparatide in serum.

• Devices used in these studies were separate iterations, and may not comprise all the same components expected in a final version.

• Rani also conducted an additional preclinical study of RaniPill HC containing Fe57 (iron) in 2 canine subjects.

• The RaniPill HC containing Fe57 showed a positive drug signal comparable to subcutaneous injection.

In October and November 2023, we announced the completion of two preclinical studies of the RaniPill HC with antibodies, adalimumab and an undisclosed anti-interleukin antibody (“Undisclosed MAB”).

In the two studies, the RaniPill HC achieved an oral delivery success rate of 100% (10/10).

In one study, we tracked the serum concentrations of adalimumab, following the oral administration of the enteric-coated RaniPill HC capsule containing 11mg of Humira (adalimumab) to four canine models.

In the second study, we tracked the serum concentrations of the Undisclosed MAB, following the oral administration of the enteric-coated RaniPill HC capsule containing 16.5mg of Undisclosed MAB to six canine models.

In both studies, the RaniPill HC was well tolerated, all animals remained healthy throughout the study period with no clinical findings or adverse events, and all device remnants were excreted normally without sequelae.

Comparing the pharmacokinetic results of 11mg of adalimumab delivered via the RaniPill HC (N=4) with historical pharmacokinetic data we generated with 5mg of an adalimumab biosimilar (GP2017) delivered via subcutaneous injection (N=3), there is a higher estimated bioavailability of adalimumab delivered via the RaniPill HC relative to the subcutaneous injection route.

Adalimumab 11mg via RaniPill HC vs Adalimumab Biosimilar 5mg via Subcutaneous Injection

All Data are Means ± SE

Pharmacokinetics of Undisclosed MAB (16.5mg) Delivered Orally via RaniPill HC Capsules to Awake Canines (N=6)

All Data are Means ± SE

Preliminary preclinical testing supports the potential for RaniPill HC to have high reliability, and initial analysis of drug delivery via the RaniPill HC shows a potential for mimicking parenteral (subcutaneous) administration.

We intend for the RaniPill HC to be ready for potential Phase 1 clinical trials in the second half of 2024.

60-Day GLP Study

We conducted a preclinical GLP study evaluating the safety and tolerability of the RaniPill drug delivery platform, following 60-day repeat oral administration of the test article, RT-100, in healthy animals.

RT-100 is an enteric-coated capsule identical to RT-102, but instead of PTH contained the pharmaceutical excipient mannitol.

The control group received a RaniPill capsule (Mock-RP) of similar weight to RT-100 but filled with potato starch.

Male and female (1:1) animals were divided into two groups and were administered either Mock-RP (N=12) or RT-100 (N=24) once daily for 60 days, with half of the animals completing an additional 14-day clinical observation and safety evaluation period.

RT-100 was well-tolerated with no treatment-related adverse events and all animals remained clinically healthy throughout the study.

Platform study in humans confirming reliable deployment in fed and fasted states

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The evaluation involved the use of capsules that were not equipped with a drug or needle.

The goals of this study were tolerability and effects of food on the RaniPill capsule’s functionality, as measured by the time required for the RaniPill capsule to reach and deploy in the small intestine.

The total transit time for the RaniPill capsule was longer in the fed group than in the fasted group because the capsule remained in the stomach longer in the fed group.

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No volunteers reported difficulty in swallowing the capsule, nor did any study participant report experiencing pain or sensing an awareness upon balloon deployment.

Our Pipeline Programs

Octreotide for the treatment of NETs and acromegaly

Market overview

Octreotide, developed by Novartis AG and sold under the brand name Sandostatin®, is a truncated and modified form of the human somatostatin.

Somatostatin is a peptide hormone involved in the regulation of the endocrine system.

It acts as an inhibitory hormone and influences hGH release, insulin and glucagon secretion, regional blood flow, gastric acid secretion, intestinal mobility, and neuronal activity.

Octreotide is a more potent mimetic with a significantly longer half-life than naturally occurring somatostatin.

Octreotide is currently approved by the FDA and EMA for the symptomatic treatment of acromegaly, a disorder involving the secretion of excessive growth hormone, as well as carcinoid syndrome, a condition involving neuroendocrine tumors (“NETs”) of the GI tract.

Current treatment using octreotide involves painful subcutaneous injections administered three to four times daily or an extended-release formulation via painful, deep intramuscular injections every four weeks.

Despite the inconvenience of the current route of administration, the worldwide market for octreotide in 2020 was approximately $2.7 billion.

A chemistry-based attempt to develop an oral version of octreotide for treatment of acromegaly (MYCAPSSA from Amryt Pharma Plc) resulted in a product with less than 1% bioavailability, which, due to this low bioavailability, was approved only for maintenance therapy of acromegaly patients on a low (100 µg) dose.

The total patient population of NETs and acromegaly in the United States is estimated to be around 200,000.

Approximately 12,000 new cases of NETs and 3,000 new cases of acromegaly are diagnosed annually in the United States.

The worldwide market for injectable somatostatin analogs is approximately $6.0 billion annually across both indications.

Our solution:

We are developing RT-101, the RaniPill capsule containing a novel formulation of octreotide, for oral treatment of NETs and acromegaly.

We have worldwide commercial rights to RT-101.

We believe that the oral delivery route provided by RT-101 has the potential to take market share from injectables and expand oral delivery of octreotide beyond the limited reach of MYCAPSSA.

Preclinical studies

RT-101 Pharmacokinetic study

Pharmacokinetic profiles of octreotide delivered as RT-101 were obtained in conscious canines, and compared to that of an equivalent intravenous (“IV”) dose of the commercially available product, Sandostatin.

All animals receiving RT-101 tolerated the oral administration of the capsule.

For the RT-101 group, the average maximum concentration (“Cmax”) was 9.9 ±

1.2 ng/ml and average time to maximum concentration (“Tmax”) for the group was 22 ±

3 minutes after payload delivery.

The average absolute bioavailability of octreotide delivered via RT-101 was 78%.

RT-101 seven-day, repeat-dose GLP study

Tolerability and reliability of RT-101 was assessed in a seven-day administration study in canines, under GLP guidelines.

RT-101 was orally administered daily to test group animals, and control group animals received an enteric-coated capsule containing nonpareil sugar.

Blood samples were collected after each RT-101 dose was administered to confirm successful payload delivery by measuring plasma concentrations of the drug.

Plasma samples analyzed from test group animals showed that 77% of the administered devices successfully delivered the drug, with seven of eight animals having at least five successful payload deliveries over the seven-day dosing period.

RT-101 was well tolerated by all animals in the study.

There were no clinical adverse effects observed in either group throughout the study duration.

The GI tract was critically evaluated in all animals and no significant macroscopic or microscopic abnormalities were observed in any animal.

These results demonstrated that the RaniPill capsule can be consumed on a daily basis for seven days, deploys within the targeted region of the small intestine without causing any adverse clinical effects, and remnants get excreted without complications.

Clinical trials

Endoscopic delivery of octreotide into the jejunum of healthy volunteers

To obtain early proof-of-concept data, we evaluated PK of Sandostatin (a commercial formulation of octreotide) delivered via a direct injection into the jejunal wall to mimic the intended route of delivery by the RaniPill capsule.

Results from this study, which involved five healthy volunteers, showed a highly similar PK profile of octreotide delivered by a direct injection into the intestinal wall to that obtained with RT-101 in its Phase 1 clinical trial.

( See below RT-101 Phase 1 study ).

These data indicate that a change in formulation of octreotide from liquid to solid form did not significantly affect the PK of the drug.

RT-101 Phase 1 study

We conducted a Phase 1 clinical trial with RT-101 in 62 healthy subjects to evaluate safety and tolerability as primary endpoints and bioavailability as a secondary endpoint.

Bioavailability of octreotide delivered via RT-101 was 65% relative to an intravenous control group.

We believe this is the first demonstration of such high bioavailability of an oral biologic in humans.

To date, the best published bioavailability for oral octreotide is approximately 1%.

The results of the RT-101 Phase 1 clinical trial support the utility of the RaniPill capsule to deliver octreotide orally, and at levels of octreotide comparable to subcutaneous injection.

In addition, the results indicate that the RaniPill capsule may be used for other biologics.

A similar study conducted in awake canines shows that the data from the canine model were consistent with the PK data obtained in humans, indicating that the canine is an appropriate model for octreotide.

Future clinical trials

We are currently optimizing the formulation for RT-101, to potentially enable once daily dosing.

Once optimized, we will test and verify the formulation in appropriate animal models.

Once the formulation is validated, we plan to initiate additional clinical trials for the development of RT-101.